CN1275977C

CN1275977C - O-aryl glucoside SGL T2 inhibitors and method

Info

Publication number: CN1275977C
Application number: CNB01807538XA
Authority: CN
Inventors: W·N·瓦斯博恩; P·M·舍尔; 吴钢
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co; Bristol Myers Squibb Pharma Co
Priority date: 2000-03-30
Filing date: 2001-03-29
Publication date: 2006-09-20
Anticipated expiration: 2021-03-29
Also published as: JP4986202B2; US20020111315A1; CA2404373A1; NO20024642D0; KR20030007488A; PL365176A1; DE60117012T2; NO20024642L; WO2001074834A1; ZA200207030B; HUP0301513A2; JP2004500416A; DE60117012D1; EP1268502B1; IL151473A0; EP1268502A1; RU2269540C2; US6683056B2; KR100798203B1; NZ520822A

Abstract

Formula (I) wherein Y is formula (a) or heteroaryl; A is -O(CH2)m, S, -NH(CH2)m, or (CH2)n where n is 0-3 and m is 0-2; and R<1> to R<6> are as defined herein. A method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above compound alone or in combination with one, two or more other antidiabetic agents, and/or one, two or more hypolipidemic agents.

Description

The O-aryl glucoside SGL T 2 inhibitors

The present invention relates to as the O-aryl glucoside that is present in the inhibitor of the sodium dependent glucose translocator (SGLT2) in intestines and the kidney, and use this class O-aryl glucoside separately or with 1,2 or more kinds of other type antidiabetic drug and/or 1,2 or more kinds of other type therapeutical agent (as hypolipidemic) combined utilization, the method of treatment diabetes, especially type ii diabetes and hyperglycemia, hyperinsulinemia, obesity, hypertriglyceridemia, X syndromes, diabetic complication, atherosclerosis and relative disease.

Nearly in the world 100,000,000 people suffer from type ii diabetes (NIDDM), it is characterized in that owing to the excessive generation of glucose in the liver and blood sugar that peripheral insulin resistance causes too highly, and its basic reason is not learnt at present as yet.It is believed that hyperglycemia is the primary hazard factor that diabetic complication produces, and directly relevant probably with the insulin secretion damage of finding among the NIDDM late period.Can predict that the normalizing of plasma glucose can be improved the effect of Regular Insulin among the NIDDM patient, and can check the development of diabetic complication.The inhibitor of sodium dependent glucose translocator SGLT2 in the expectation kidney helps the normalizing of plasma glucose levels by increasing the drainage of glucose, and the normalizing that perhaps helps body weight.

For replenishing existing therapy, also require new, the safe and oral active antidiabetic of development, comprise sulfonylurea, thiazolidinedione, N1,N1-Dimethylbiguanide and Regular Insulin, and combine application with these other medicines, avoid the potential side effect.

Hyperglycemia is the sign of type ii diabetes (NIDDM); The plasma glucose levels of stablizing control of diabetes can be checked visible β cellular degeneration in the development of diabetic complication and the terminal illness.Under the plasma glucose normal circumstances at kidney mesonephric glomerulus inner filtration, and at the proximal tubule tubule by active absorption.It seems that SGLT2 be that the re-absorbed main translocator of glucose is responsible at this position.SGLT specific inhibitor phlorizin or its closely-related analogue can suppress this absorption process again of diabetes rodent and dog by promoting the drainage of glucose, make plasma glucose levels normalizing, and do not have hypoglycemic side effect.Reported diabetes rat with SGLT2 inhibitor long-term (6 months) treatment Zucker, can improve insulin response to blood sugar, improve insulin sensitivity, and postpone ephrosis and the neuropathic generation of these animals, simultaneously kidney not being had can detected illness, and blood plasma is not had the electrolyte imbalance effect.Can expect that selectivity suppresses diabetic subject's SGLT2, can make plasma glucose normalizing, therefore improve insulin sensitivity, and postpone the generation of diabetic complication by the drainage that strengthens glucose in the urine.

The absorbing again in the epithelial cell that occurs in the S1 sections that the renal cortex proximal tubule begins of glucose in 90% kidney, SGLT2 is responsible for this resorbent main translocator.SGLT2 is 672 amino acid whose protein that contain 14 TMDs, and it mainly is expressed on the S1 sections that the kidney proximal tubule begins.The substrate specificity of SGLT2, sodium dependency and location are consistent with the character of the heavy body of the previous people's renal cortex proximal tubule that characterizes, low affinity, sodium dependent glucose translocator.In addition, crossbred is exhausted the research hint, and SGLT2 is main Na in the proximal tubule S1 sections ⁺/ glucose cotransporter, reason are that all sodium dependent glucose transport activities of in fact encoding among the renocortical mRNA of rat all can be had specific antisense oligonucleotide to rat SGLT2 and suppress.SGLT2 is the candidate gene of some familial glucosuria form, and the familial glucosuria is that a kind of kidney glucose absorbs the hereditary disorder that has in various degree damage again.These syndromes of being investigated so far SGLT2 locus to karyomit(e) 16 of not mapping as yet.But, to the research of height homologous rodent SGLT hint: SGLT2 sodium dependency translocator in the main kidney of glucose, and prompting, the Portugal that has mapped urine locus a kind of SGLT2 conditioning agent of encoding.Can foretell, suppress SGLT2 and can reduce plasma glucose levels by the drainage that strengthens diabetic subject's glucose.

SGLT1 is another kind of sodium dependent glucose cotransporter, and it is 60% identical with SGLT2 on amino acid levels, and it is expressed in small intestine and kidney proximal tubule more in the S3 sections in distally.Although the sequence similarity of people SGLT1 and SGLT2, there is difference in they on biological chemistry.For SGLT1, Na ⁺With the mol ratio of the glucose of being transported be 2: 1, and for SGLT2, this ratio is 1: 1.SGLT1 and SGLT2 are for Na ⁺K _mBe respectively 32mM and 250-300mM.SGLT1 and SGLT2 are for the K of glucose and non-metallic glucalogue Alpha-Methyl-D-pyrans heteroside (AMG) picked-up _mBe worth similarly, promptly the value of SGLT1 and SGLT2 translocator is respectively 0.8 and 1.6mM (glucose) and 0.4 and 1.6mM (AMG).But these two kinds of translocators are different on the substrate specificity of its sugar (as semi-lactosi), and semi-lactosi is the substrate of SGLT1.

In several diabetes rodent models and a kind of diabetes canine model, give phlorizin-active specific inhibitor of a kind of SGLT, can promote the utilization that glucose is drained, reduced the fasting plasma glucose and take the photograph plasma glucose and promote glucose, do not have the hypoglycemia side effect simultaneously, this provides evidence for theory in the body.Reached for two weeks with the phlorizin treatment, the result does not find that plasma ion balance, renal function or renomorphology are had side effect.In addition, when giving the intact animal phlorizin,, do not observe hypoglycemia or other side effect although there is glucosuria.Be reported in the fat NIDDM rat model, give kidney SGLT inhibitor reach 6 months (Tanabe Seiyaku) can improve the fasting plasma glucose and ingest plasma glucose, improve secretion of insulin and utilization, and can check ephrosis and neuropathic generation, there is not the generation of hypoglycemia or kidney side effect simultaneously.

As oral pharmaceutical, phlorizin itself is not noticeable, and reason is that it is non-specific SGLT1/SGLT2 inhibitor, can be hydrolyzed to its aglycone-phloretin in intestines, and the latter is effective inhibitor of facilitation glucose transport.Owing to think that the inhibitor of facilitation glucose transporter may increase the weight of peripheral insulin resistance and promote hypoglycemia among the CNS, so such inhibition (GLUT) at present is nonconforming.Suppress SGLT1 and also may produce severe side effect, heredity glucose/semi-lactosi malabsorption (GGM) syndromes has illustrated this point, and wherein the sudden change of SGLT1 cotransporter causes impaired and life-threatening diarrhoea of glucose absorption and dehydration in the intestines.Biological chemistry difference between SGLT2 and the SGLT1 and the degree of sequence divergence can be for the usefulness of identifying selectivity SGLT2 inhibitor between them.

Familial glucosuria syndromes is glucose transport and interior other ion of kidney and the normal illness of amino acid transport in the intestines.As if although glucose is drained the height (110-114g/ day) of being on close level sometimes, familial glucosuria patient it seems and grows normally, has normal plasma glucose levels, and do not present big healthy defective because of its disease.Tangible cardinal symptom comprises voracity, diuresis and extremely kind thirsty among these patients, and kidney seems normally on 26S Proteasome Structure and Function.Therefore, from finding the existing fact so far, as if in the normal individuality of others, the resorbent defective of the kidney of glucose has minimum long-term negative consequences.

Following reference discloses the O-aryl glucoside SGL T 2 inhibitors that is used for the treatment of diabetes.

EP 598359A1 (also being JP 035988) (Tanabe Seiyaku) discloses the compound with following structure A.

R ¹=H, acyl group R ²=H, MeR ⁴, R ⁴Can be various substituting groups

EP 0850948A1 discloses has following classification BThe compound of structure.

R ¹=H, acyl group, CO (O alkyl) R ²=H, allyl group R ³=H or Me

JP 091 88625A structure BOn expand, to comprise wherein R ³Be H, wherein these 5 yuan of rings are saturated rings BEmbodiment and thionaphthene (O=S) and indenes (O=CH ₂) counterpart.

R ¹=H, acyl group, CO (O alkyl) R ²=H, allyl group R ³=H or Me

JP 09124685A is at R ³The structure of=H BOn expand, with, comprise the derivative of C6 hydroxyl monoacylation, wherein this acyl group is the phenylformic acid that replaces or pyridine carboxylic acid or the urethane that produced by the phenol of correspondence.

R ¹=H, acyl group aryl, CO (O alkyl) R ²=H

JP 09124684 discloses structure BDerivative.

R ²=H, alkyl, alkoxyl group, aryl or be the oxo base together

EP 773226-A1 discloses structure BDerivative.

If R ²=H, then R ¹If=alkyloyl R ¹= ^H, R then ²=carbalkoxy

JP 08027006-A discloses structure ADerivative, wherein, similar with EP 598359A1 with the various combination acylations of various glucose hydroxyls.

EP 684254-A1 comprises disclosed structure among the JP 09188625A BDerivative.

The publication and the publication of other open SGLT2 inhibitor are as follows:

K.Tsujihara etc., Chem.Pharm.Bull.44,1174-1180 (1996)

M.Hongu etc., Chem.Pharm.Bull.46,22-23 (1998)

M.Hongu etc., Chem.Pharm.Bull.46,1545-1555 (1998)

A.oku etc., Diabetes.48,1794-1800 (1999)

JP 10245391 (Dainippon) discloses 500 structural compounds as Hypoylycemic agents that are used for the treatment of diabetes.They are O-glucosides of hydroxylation tonka bean camphor.

Other reference for open O-aryl glucoside structure shown below, they and classification disclosed by the invention are closely related:

1) G.K.Jain etc., Indian J.Chem.26B, 163-166 (1989)

2) A.Levai etc., Acta Chim.Acad.Sci.Hung., 84,99-107 (1975)

3) H.Kaemmerer etc., Makromol.Chem.182,1351-1361 (1981)

The description of invention

The invention provides a kind of O-aryl glucoside compound and pharmacy acceptable salt, its all steric isomer and all prodrug esters thereof with following formula structure I:

Wherein

When Y is

Perhaps during heteroaryl;

R ², R ², R ³And R ⁴Identical or different, independently be selected from hydrogen, OH, OR ⁷, low alkyl group or halogen, perhaps R ², R ², R ³And R ⁴In two coupled carbon atoms can form condensed 5,6 or 7 yuan of carbocyclic rings or heterocycles together, it can contain 1-4 and be N, O, S, SO and/or SO in ring ₂Heteroatoms;

R ⁵And R ⁶Identical or different, independently be selected from hydrogen, OH, OR ^7a,-O aryl ,-OCH ₂Aryl, low alkyl group, cycloalkyl, aryl, arylalkyl, CF ₃, aromatic yl alkenyl ,-OCHF ₂,-OCF ₃, halogen ,-CN ,-CO ₂R ^7b,-CO ₂H, COR ^8f, CHOHR ^8g, CH (OR ^7h) R ^8h,-CONR ⁸R ^8a,-NHCOR ^7c,-NHSO ₂R ^7d,-NHSO ₂Aryl ,-SR ^7e,-SOR ^7f,-SO ₂R ^7g,-SO ₂Aryl ,-OCH ₂CO ₂R ⁷ⁱ,-OCH ₂CO ₂H ,-OCH ₂CONR ^8bR ^8c,-OCH ₂CH ₂NR ^8dR ^8e, or in ring, can contain 1-4 and be N, O, S, SO and/or SO ₂Heteroatomic 5,6 or 7 yuan of heterocycles, perhaps R ⁵And R ⁶Coupled carbon atom forms condensed 5,6 or 7 yuan of carbocyclic rings or heterocycles together, and it can contain 1-4 and be N, O, S, SO and/or SO in ring ₂Heteroatoms;

R ⁷, R ^7a, R ^7b, R ^7c, R ^7d, R ^7e, R ^7f, R ^7g, R ^7hAnd R ⁷ⁱIt independently is low alkyl group;

R ⁸, R ^8a, R ^8b, R ^8c, R ^8d, R ^8e, R ^8f, R ^8gAnd R ^8hIdentical or different, independently be selected from hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, perhaps coupled nitrogen-atoms is formed on together and can contains 1-4 in the ring and be N, O, S, SO and/or SO ₂5,6 or 7 yuan of heterocycles of heteroatomic condensed;

A is O (CH ₂) _m, S, NH (CH ₂) _mPerhaps (CH ₂) _n, wherein n is 0-3, m is 0-2.

More than Ding Yi formula I compound of the present invention also comprises following condition:

Wherein A is CH ₂And Y is

And

1) works as R ¹Be OH, R ³When being alkyl, R ², R ⁴, R ⁵And R ⁶At least one of them is not a hydrogen, and 4-R ^bPreferably not hydrogen;

2) work as R ²And R ³When being OH, R ², R ⁴, R ⁵And R ⁶At least one of them is not a hydrogen, and 4-R ⁶Preferably not hydrogen;

3) work as R ²Be methyl, R ⁵Be OH, R ⁶When being alkyl, R ¹, R ³And R ⁴At least one of them is not a hydrogen; And

4) work as R ²When being chlorine, R ¹, R ³, R ⁴, R ⁵And R ⁶At least one of them is not a hydrogen, and 4-R ⁶Preferably not hydrogen.

In formula I compound, wherein A is O (CH ₂) _mOr NH (CH ₂) _m, heteroatoms O or N link to each other with aryl rings direct and that glucoside partly is connected.

Formula I compound of the present invention has as the activity that is present in the inhibitor of the sodium dependent glucose translocator in mammal intestine and the kidney, can be used for treating the capillary blood vessel and the great vessels complication of diabetes and diabetes, as retinopathy, neuropathy, ephrosis and wound healing.

The method of the invention provides formula I compound, utilizing the medicinal compositions of these compounds and use these compounds.

In addition, the invention provides a kind of method for the treatment of following disease and improving hdl level: diabetes, especially type ii diabetes and relative disease, comprise diabetic complication, comprise retinopathy, neuropathy, ephrosis and wound healing, and the blood plasma level of relative disease such as insulin resistant, hyperglycemia, hyperinsulinemia, X syndromes, lipid acid or glycerine increases, obesity, hypertriglyceridemia, atherosclerosis and hypertension, wherein needs the structure I compound of the present invention of the patient treatment significant quantity of this kind treatment.

In addition, the invention provides a kind of diabetes and above and for the treatment of, wherein need the structure I compound of the present invention and 1,2 or more kinds of other type antidiabetic drug and/or 1,2 or the combination of the therapeutical agent of more kinds of other types of the human patients treatment significant quantity of this kind treatment with the method for undefined relative disease.

Illness, disease and illness that system is referred to as " X syndromes " (being also referred to as metabolic syndrome) can see Johannsson J.Clin.Endocrinol.Metab. for details, and 82,727-34 (1997).

Term used herein " therapeutical agent of other type " is meant the medicine (comprising antiatherosclerotic) of one or more antidiabetic drug (except the SGLT2 inhibitor of formula I), the sick medicine of one or more anti-obesity and/or one or more blood fat reducing.

In above the inventive method, the weight ratio (deciding) of used structure I compound and antidiabetic drug and/or blood fat reducing medicine according to use-pattern at about 0.01: 1 to about 300: 1 scope, preferred about 0.1: 1 to about 100: 1 scope, and more preferably from about 0.1: 1 to about 10: 1 scope.

Preferred formula IA compound

Wherein A is CH ₂Or O or S.

More preferably formula IA compound, wherein A is CH ₂

R ¹Be H, halogen or alkyl;

R ², R ³Each is hydrogen naturally;

R ⁵Be hydrogen.

The formula I compound of most preferred configuration IB

R wherein ¹Be H, halogen or alkyl, perhaps R ²And R ⁴It independently is hydrogen or alkyl;

R ⁶Be H, alkyl, R ^7aO, CHF ₂O, CF ₃O or R ^7eS.

The preferred formula I examples for compounds of the present invention comprises the compound with following structure:

^*R ⁶=H, except as otherwise noted

A	R ¹	R ²	R ³	R ⁴	R ⁵
A	R ¹	R ²	R ³	R ⁴	R ⁵	CH ₂	H	H	H	H	4-MeO
CH ₂	H	H	H	H	4-tBu	CH ₂	H	H	H	H	4-MeO
CH ₂	H	H	H	H	4-tBu	CH ₂	H	H	H	H	4-MeS
CH ₂	H	H	H	H	4-iPr	CH ₂	H	H	H	H	4-MeS
CH ₂	H	H	H	H	4-iPr	CH ₂	H	H	H	H	4-Cl
CH ₂	H	H	H	H	4-CF ₃	CH ₂	H	H	H	H	4-Cl
CH ₂	H	H	H	H	4-CF ₃	CH ₂	H	H	H	H	4-CF ₃O
CH ₂	Me	H	H	H	H	CH ₂	H	H	H	H	4-CF ₃O
CH ₂	Me	H	H	H	H	CH ₂	H	H	H	Me	4-MeS
CH ₂	H	H	H	Me	4-Me	CH ₂	H	H	H	Me	4-MeS
CH ₂	H	H	H	Me	4-Me	CH ₂	Cl	H	H	H	H

Formula I compound of the present invention can be according to following reaction process and explanation preparation thereof, and wherein temperature is with a degree centigrade expression.

Formula I compound of the present invention can be used formula II compound

By at solvent as 3: 1 MeOH/H ₂O or 3: 2: 1 MeOH/THF/H ₂Among the O, with alkali such as LiOH or NaOH Processing of Preparation.

Formula II compound can pass through at Ag ₂Under existing, O in solvent such as lutidine or quinoline, perhaps in the presence of silver trifluoromethanesulfonate, containing alkali, the solvent such as the CH of 6-di-t-butyl-4-picoline as 2 ₂Cl ₂In, make commercially available 2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromine III

With formula IV compound prepared in reaction.

Flow process I

(wherein A is (CH to formula IV compound ₂) _n(n=1-3)), available formula V compound

By in solvent such as MeOH or EtOH, in the presence of catalyzer such as Pd/C, use H ₂Processing of Preparation.

Formula V compound or by commercially available, the perhaps the whole bag of tricks of being familiar with by those skilled in the art is by with formula VI compound

Prepare with formula VII compound acylations.

(wherein A is (CH to formula IV compound ₂) ₂), available commercially available formula VIII compound

(wherein A is CH to formula IV compound ₂), can adopt solvent (as toluene) and alkali (as NaH), by with formula VI compound with commercially available formula IX compound

Alkylation preparation, condition are the aryl of IX or heteroaryl ring not electron deficiency, i.e. substituent R ⁵And R ⁵Total Hammet σ not low～+ 0.3.

(wherein A is CH to formula IV compound ₂), also available formula X compound

By in solvent such as MeOH or EtOH, in the presence of catalyzer such as Pd/C, use H ₂Processing of Preparation, perhaps at solvent as containing Lewis acid (as TFA or BF ₃Et ₂O) among the MeCN, with silane such as Et ₃The SiH preparation.

Formula X compound, the whole bag of tricks that can be familiar with by those skilled in the art is by making commercially available formula XI compound

With Mg ²⁺Or Li ⁺The preparation of organo-metallic ionic reaction, this organo-metallic ion is by aryl or heteroaryl bromine or the chlorine preparation of formula XII

XII

Br-Y。

See shown in the flow process 2 that formula IV compound (wherein A is O) also can adopt catalyzer such as Pd/C, with formula XIII compound by in solvent such as MeOH or EtOH

Use H ₂Processing of Preparation.Formula XIII compound can be by containing Et ₃N, molecular sieve and Cu (OAc) ₂Solvent such as pyridine in, make formula XIV compound

With formula XV compound prepared in reaction.

Formula XIV compound or by commercially available, the perhaps method of being familiar with by those skilled in the art is by with corresponding catechol XVI

Its bromotoluene or chlorine alkylation with monovalent is prepared.

Formula XV compound is provided by commercially available, perhaps can be under-75 ℃, at solvent such as CH ₂Cl ₂In, with XVII BCl ₃Processing of Preparation.

Formula XVII compound can be by containing catalyzer (as PdCl ₂Dppf) and in the solvent such as DMSO of alkali (as KOAc), with formula XII compound

VIII adds hot preparation with compounds X.

Flow process 2

(wherein A is OCH to formula IV compound ₂), promptly

Can be by containing alkali (as Na ₂CO ₃) and the polar solvent such as DMF or acetone of catalyzer (as NaI) in, make formula XVI compound and formula IXa benzyl halide prepared in reaction.

(wherein A is O (CH to formula IV compound ₂) ₂), can adopt catalyzer such as Pd/C by in solvent such as MeOH or EtOH, make formula XIX compound

With H ₂Prepared in reaction.Formula XIX compound can be provided by commercially available, perhaps can be by containing alkali (as K ₂CO ₃) solvent such as acetone in, with commercially available formula XX phenacyl chloride or bromine, formula XVI alkylation is prepared.

Formula IV compound (wherein A is S) can be by under-78 ℃, in solvent such as THF, with formula XXI compound

Handle with 2 normal t-BuLi, add formula XXII compound then.

See shown in the flow process 3 that formula II compound (wherein A is NH) can be by containing Cu (OAc) ₂Solvent such as Et with molecular sieve ₃Among the N, with formula XXIII compound

Prepare with formula XV compound treatment.

Formula XXIII compound can adopt catalyzer such as Pd/C, with formula XXIV compound by in solvent such as MeOH or EtOH

Use H ₂Processing of Preparation.

Formula XXIV compound can be by containing Ag ₂In the solvent of O such as lutidine or the quinoline, with formula III compound and formula XXV compound coupling preparation.

Flow process 3

A＝NH

(wherein A is NHCH to formula II compound ₂), can be by stirring down, in solvent such as HOAc, with reductive agent such as NaCNBH ₃, with formula XXIII compound and formula XXVI compound coupling preparation.

(wherein A is NHCH to formula II compound ₂CH ₂), can be by stirring down, in solvent such as HOAc, with reductive agent such as NaCNBH ₃, with formula XXIII compound and formula XXVII compound coupling preparation.

Below list the definition of the various terms that are used to describe The compounds of this invention.These definition be applicable in this specification sheets the term that uses separately or use as the part of macoradical (except that have in addition under specific circumstances limit).

The used abbreviation of the present invention is as follows:

The Ph=phenyl

The Bn=benzyl

The t-Bu=tertiary butyl

The Me=methyl

The Et=ethyl

TMS=three silyls

TMSN ₃=azide three silicomethanes

TBS=tertiary butyl dimethyl silanyl

The THF=tetrahydrofuran (THF)

Et ₂The O=ether

The EtOAc=ethyl acetate

The DMF=dimethyl formamide

MeOH=methyl alcohol

EtOH=ethanol

The i-PrOH=Virahol

HOAc or AcOH=acetate

The TFA=trifluoroacetic acid

I-Pr ₂The NEt=diisopropylethylamine

Et ₃The N=triethylamine

The DMAP=4-Dimethylamino pyridine

NaBH ₄=sodium borohydride

LiAlH ₄=lithium aluminum hydride

The n-BuLi=n-Butyl Lithium

The Pd/C=palladium on carbon

KOH=potassium hydroxide

NaOH=sodium hydroxide

The LiOH=lithium hydroxide

K ₂CO ₃=salt of wormwood

NaHCO ₃=sodium bicarbonate

EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or EDAC=3-ethyl-3 '-(dimethylamino) propyl group-carbodiimide hydrochloride (or 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride)

HOBT or HOBT.H ₂The O=1-hydroxy benzotriazole hydrate

HOAT=1-hydroxyl-7-azepine benzotriazole

Ph ₃The P=triphenyl phosphine

Pd (OAc) ₂=acid chloride

(Ph ₃P) ₄Pd ⁰=four (triphenyl phosphine) palladium

The Ar=argon gas

N ₂=nitrogen

Min=minute

H or hr=hour

The L=liter

The mL=milliliter

μ L=microlitre

The g=gram

The mg=milligram

The mol=mole

The mmol=mmole

The meq=milliequivalent

The RT=room temperature

Sat or sat ' d=are saturated

The aq.=aqueous solution

The TLC=thin-layer chromatography

The HPLC=high performance liquid chromatography

LC/MS=high performance liquid chromatography/mass spectrum

MS or Mass Spec=mass spectrum

The NMR=nucleus magnetic resonance

The mp=fusing point

Dppf=diphenyl phosphine ferrocene

DCE=1, the 2-ethylene dichloride

Unless otherwise indicated, the term " low alkyl group " that the part of independent use or the other group of conduct is used among the present invention, " alkyl " or " alk " comprises the direct sum branched-chain hydrocarbon, in this straight chain, contain 1-20 carbon atom, preferred 1-10 carbon atom, more preferably 1-8 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, isohexyl, heptyl, 4,4-dimethyl amyl group, octyl group, 2,2, the 4-tri-methyl-amyl, nonyl, decyl, undecyl, dodecyl and various branched chain isomers etc. thereof, and comprise 1-4 substituent this class group, substituting group such as halo, for example F, Cl, Br or I or CF ₃Alkyl; alkoxyl group; aryl; aryloxy; aryl (aryl) or diaryl; arylalkyl; alkoxy aryl; alkenyl; alkynyl group; cycloalkyl; cycloalkenyl group; cycloalkylalkyl; cycloalkyl alkoxy; the optional amino that replaces; hydroxyl; hydroxyalkyl; acyl group; oxo; alkyloyl; heteroaryl; heteroaryloxy; the assorted alkyl of ring; the aryl heteroaryl; aryl alkyl carbonyl oxygen; heteroarylalkyl; the heteroaryl alkoxyl group; aryloxy alkyl; the aryloxy aryl; alkylamidoalkyl; alkyl amido; aryl-amino-carbonyl; nitro; cyano group; thiol group; haloalkyl; tri haloalkyl and/or alkylthio.

Unless otherwise indicated, use separately among the present invention or comprise saturated or part is unsaturated (containing 1 or 2 two key) contains 1-3 the cyclic hydrocarbon group of encircling as the term " cycloalkyl " that the part of group is in addition used, comprise monocycle alkyl, bicyclic alkyl and tricyclic alkyl, it comprises that altogether 3-20 becomes ring carbon atom, preferred 3-10 becomes ring carbon atom, and can with 1 or 2 aryl item down the aromatic ring of explanation condense, it comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring decyl and cyclo-dodecyl, cyclohexenyl,

Any above-mentioned group can be chosen the group that is replaced by 1-4 substituting group, substituting group such as halogen, alkyl, alkoxyl group, hydroxyl, aryl, aryloxy, arylalkyl, cycloalkyl, alkyl amido, alkyl amide, oxo, acyl group, aryl-amino-carbonyl, amino, nitro, cyano group, thiol group and/or alkylthio and/or any alkyl substituent wantonly.

Unless otherwise indicated, use separately among the present invention or refer to contain 3-12 carbon atom as the term " cycloalkenyl group " that the part of group is in addition used, preferred 5-10 carbon atom, and contain the cyclic hydrocarbon of 1 or 2 pair of keys.The example of cycloalkenyl group comprises cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclohexadienyl and cycloheptadiene base, and it can illustrate optional being substituted down by the cycloalkanes ground term.

The alkyl that uses separately among the present invention or refer to as the term " alkyloyl " that the part of group is in addition used to be connected with carbonyl.

Unless otherwise indicated; the term " low-grade alkenyl " or " alkenyl " that use separately among the present invention or use as the part of other group refer to contain 2-20 carbon atom in this straight chain; preferred 2-12 carbon atom; the more preferably straight chain of 1-8 carbon atom and branched group; it comprises 1-6 two key in straight chain; as vinyl; the 2-propenyl; the 3-butenyl; crotyl; the 4-pentenyl; the 3-pentenyl; the 2-hexenyl; the 3-hexenyl; the 2-heptenyl; the 3-heptenyl; the 4-heptenyl; the 3-octenyl; 3-nonene base; 4-decene base; 3-hendecene base; 4-laurylene base; 4; 8; 12-tetradecane trialkenyl etc.; it can be chosen wantonly by 1-4 following substituent replacement, and substituting group is a halogen; haloalkyl; alkyl; alkoxyl group; alkenyl; alkynyl group; aryl; arylalkyl; cycloalkyl; amino; hydroxyl; heteroaryl; the assorted alkyl of ring; alkanoylamino; alkylamidoalkyl; aryl-amino-carbonyl; nitro; cyano group; thiol group; any alkyl substituent that alkylthio and/or the present invention propose.

Unless otherwise indicated; the term " alkynyl of low-grade chain " or " alkynyl group " that use separately among the present invention or use as the part of other group refer to contain 2-20 carbon atom in this straight chain; preferred 2-12 carbon atom; the more preferably straight chain of 2-8 carbon atom and branched group; it comprises 1 triple bond in straight chain; as 2-propynyl; the 3-butynyl; the 2-butyne base; the 4-pentynyl; the 3-pentynyl; 2-hexin base; 3-hexin base; 2-heptyne base; 3-heptyne base; 4-heptyne base; 3-octyne base; 3-n-heptylacetylene base; the 4-decynyl; 3-undecyne base; 4-dodecyne base etc.; and it can be chosen wantonly by 1-4 following substituent replacement, and substituting group is a halogen; haloalkyl; alkyl; alkoxyl group; alkenyl; alkynyl group; aryl; arylalkyl; cycloalkyl; amino; heteroaryl; the assorted alkyl of ring; hydroxyl; alkanoylamino; alkylamidoalkyl; aryl-amino-carbonyl; nitro; cyano group; any alkyl substituent that thiol group and/or alkylthio and/or the present invention propose.

Use separately or refer to have alkyl, alkenyl and the alkynyl group of the above explanation of aryl substituent among the present invention as term " arylalkyl ", " aromatic yl alkenyl " and " aryl alkynyl chain " that the part of group is in addition used.

When the singly-bound that alkyl has on two different carbon atoms with other group is connected of above definition, be called " alkylidene group ", it can explanation be optional down be substituted by above " alkyl ".

When the alkenyl of above definition has the singly-bound that is connected usefulness respectively with alkynyl group on two different carbon atoms, be called " alkylene group " and " inferior alkynyl group " respectively, it can illustrate optional being substituted down by above " alkenyl " and " alkynyl group " item.

Suitable alkylidene group, alkylene group or inferior alkynyl group (CH ₂) _m, (CH ₂) _nOr (CH ₂) _p(wherein p can be 1-8, preferred 1-5, it comprises alkylidene group, alkylene group or the inferior alkynyl group of definition herein) can be chosen wantonly and comprise that 1,2 or 3 comprises alkyl, alkenyl, halogen, cyano group, hydroxyl, alkoxyl group, amino, alkylthio, ketone group, C ₃-C ₆The substituting group of cycloalkyl, alkyl-carbonyl-amino or alkyl-carbonyl oxygen base.

(CH ₂) _m, (CH ₂) _nOr (CH ₂) _p, alkylidene group, alkylene group and inferior alkynyl group example comprise-CH ₂-,-CH ₂CH ₂-,-CH=CH-CH ₂-,-CH ₂CH=CH-,-C ≡ C-CH ₂-,

-CH ₂C≡CCH ₂-，

-(CH ₂) ₂-，-(CH ₂) ₃-，-(CH ₂) ₄-，

-(CH ₂) ₅-，

-CH ₂OCH ₂-，-OCH ₂CH ₂-，-CH ₂NHCH ₂-，

-NHCH ₂CH ₂-,-(CH ₂) ₃-CF ₂-,

Or

The term " halogen " or " halo " that use separately among the present invention or use as the part of other group refer to chlorine, bromine, fluorine and iodine, preferred chlorine or fluorine.

Term " metal ion " refers to alkalimetal ion such as sodium, potassium or lithium and alkaline-earth metal ions such as magnesium and calcium and zinc and aluminium.

Unless otherwise indicated, use separately among the present invention or refer to contain the monocycle of 6-10 carbon atom and bicyclic aromatic group (as phenyl or naphthyl at loop section as the term " aryl " that the part of group is in addition used, comprise 1-naphthyl and 2-naphthyl), it can be chosen wantonly and comprise 1-3 and carbocyclic ring or heterocycle (as the assorted alkyl ring of aryl, cycloalkyl, heteroaryl or ring) other ring of condensed, for example

And can be optional by 1 by available carbon atom; 2 or 3 are selected from following substituting group replacement, and substituting group is a hydrogen; halogen; haloalkyl; alkyl; haloalkyl; alkoxyl group; halogenated alkoxy; alkenyl; trifluoromethyl; trifluoromethoxy; alkynyl group; cycloalkyl-alkyl; the assorted alkyl of ring; the assorted alkyl-alkyl of ring; aryl; heteroaryl; arylalkyl; aryloxy; aryloxy alkyl; alkoxy aryl; carbalkoxy; aryl carbonyl; aromatic yl alkenyl; the aminocarboxyl aryl; arylthio; aryl sulfonyl kia; the arylazo base; heteroarylalkyl; the heteroaryl alkenyl; the heteroaryl heteroaryl; heteroaryloxy; hydroxyl; nitro; cyano group; amino; wherein this amino comprises that 1 or 2 substituting group (is alkyl; any other aryl compound of mentioning in aryl or the above definition) substituted-amino; thiol group; alkylthio; arylthio; heteroarylthio; arylthio alkyl; the alkoxy aromatic sulfenyl; alkyl-carbonyl; aryl carbonyl; alkyl amino-carbonyl; aromatic yl aminocarbonyl; carbalkoxy; aminocarboxyl; the alkyl-carbonyl oxygen base; aryl carbonyl oxygen base; alkyl-carbonyl-amino; aryl-amino-carbonyl; aryl sulfonyl kia; the aryl sulfonyl kia alkyl; any alkyl substituent that Arenesulfonyl amino or aryl sulfonyl amino carbonyl and/or the present invention propose.

Unless otherwise indicated, use separately among the present invention or as term " lower alkoxy ", " alkoxyl group ", " aryloxy " or " aralkoxy " that the part of group is in addition used refer to be connected with Sauerstoffatom any more than alkyl, aralkyl or aryl.

Unless otherwise indicated, the term " amino of replacement " that uses separately among the present invention or use as the part of other group refers to have one or two identical or different substituent substituted-amino, substituting group such as alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, the assorted alkyl of ring, the assorted alkyl-alkyl of ring, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or alkylthio.These substituting groups can further be replaced by monocarboxylic acid and/or any alkyl substituent set forth above.In addition, described amino substituting group can be coupled nitrogen-atoms form 1-pyrrolidyl, piperidino, 1-azepine _ base, 4-morpholinyl, 4-thio-morpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-alkyl diaryl-1-piperazinyl, 1-pyrrolidyl, piperidino or 1-azepine _ base together, they are optional to be replaced by alkyl, alkoxyl group, alkylthio, halo, trifluoromethyl or hydroxyl.

Unless otherwise indicated, use separately among the present invention or as term " lower alkylthio ", " alkylthio ", " arylthio " or " aromatic alkylthio " that the part of group is in addition used refer to be connected with sulphur atom any more than alkyl, aralkyl or aryl.

Unless otherwise indicated, use separately among the present invention or as term " low-grade alkyl amino ", " alkylamino ", " arylamino " or " aryl alkyl amino " that the part of group is in addition used refer to be connected with nitrogen-atoms any more than alkyl, aryl or aralkyl.

Unless otherwise indicated, the organic group that uses separately among the present invention or refer to as the term " acyl group " that the part of group is in addition used to be connected with carbonyl (C=O); The acyl group example comprises any alkyl substituent that is connected with carbonyl, as alkyloyl, alkenoyl, aroyl, aralkanoyl, 4-hetaroylpyrazol, cycloalkanes acyl group, the assorted alkyloyl of ring etc.

Unless otherwise indicated, 5-, the 6-or the first saturated or unsaturated ring of part of 7-that use separately among the present invention or refer to comprise 1-2 heteroatoms (as nitrogen, oxygen and/or sulphur), connect by carbon atom or heteroatoms as the term " the assorted alkyl of ring " that the part of group is in addition used, if possible, optional by joint (CH ₂) _pConnect (wherein p is 1,2 or 3), as

Above group can comprise 1-4 substituting group, as the alkyl substituent of alkyl, halo, oxo and/or any the present invention proposition.In addition, the assorted alkyl ring of any ring can condense with the assorted alkyl ring of cycloalkyl, aryl, heteroaryl or ring.

Unless otherwise indicated, use or refer to comprise the 5-or the 6-unit aromatic ring of 1,2,3 or 4 heteroatoms (as nitrogen, oxygen and/or sulphur) among the present invention separately as the term " heteroaryl " of the part use of group in addition, this ring can condense (as benzothienyl, indyl) with the assorted alkyl ring of aryl, cycloalkyl, heteroaryl or ring, and may comprise the N-oxide compound.This heteroaryl can be chosen wantonly and comprise 1-4 substituting group, as any alkyl substituent set forth above.The example of heteroaryl comprises following groups etc.:

The term that the part of independent use or the other group of conduct is used among the present invention " encircles the alkyl-alkyl of mixing " and refers to by C atom or heteroatoms and (CH ₂) _pThe assorted alkyl of the ring of the above definition that chain connects.

The term " heteroarylalkyl " that uses separately among the present invention or use as the part of group in addition or " heteroaryl alkenyl " refer to by C atom or heteroatoms and-(CH ₂) _pThe heteroaryl of the above definition that the alkylidene group of-chain, above definition or alkylene group connect.

Term used herein " 5,6 or 7 yuan carbocyclic ring or heterocycle " is meant the cycloalkyl of above definition or the heteroaryl or the ring heteroaryl of cycloalkenyl group or above definition, as thiadiazolyl group, tetrazyl, imidazolyl Huo oxazolyl.

Term used herein " multi-haloalkyl " is meant and comprises 2-9, preferred 2-5 halo substituting group, and as F or Cl, " alkyl " of the above definition of preferred F is as CF ₃CH ₂, CF ₃Or CF ₃CF ₂CH ₂

Term used herein " many halogenated alkoxies " is meant and comprises 2-9, preferred 2-5 halo substituting group, and as F or Cl, " alkoxyl group " or " alkyl oxy " of the above definition of preferred F is as CF ₃CH ₂O, CF ₃O or CF ₃CF ₂CH ₂O.

Term used herein " prodrug ester " comprises the method for using generation acetic ester well known by persons skilled in the art, pivalate, methyl carbonic, benzoic ether etc., the ester and the carbonic ether of the acylating reagent reaction formation that replaces by one or more hydroxyl and alkyl, alkoxyl group or the aryl that makes formula I compound.In addition, also have carboxylic acid known in the art and phosphoric acid ester, as prodrug esters such as methyl esters, ethyl ester, benzyl esters.

The example of these prodrug esters comprises CH ₃CO ₂CH ₂-, T-C ₄H ₉CO ₂CH ₂-, or

Suitably other example of prodrug ester comprises

R wherein ^aCan be H, alkyl (as the methyl or the tertiary butyl), arylalkyl (as benzyl) or aryl (as phenyl); R ^dBe H, alkyl, halogen or alkoxyl group, R ^eBe alkyl, aryl, arylalkyl or alkoxyl group, n ₁Be 0,1 or 2.

When the structure I compound is sour form, they can form pharmacy acceptable salt, as an alkali metal salt (as lithium, sodium, potassium), alkaline earth salt (as magnesium and calcium) and zinc and aluminium and other positively charged ion, as ammonium, choline, diethanolamine, Methionin (as D and L), 1,2 quadrol, tert-butylamine, uncle's octyl amine, three (methylol) aminomethane (TRIS), N-methylglucosamine (NMG), trolamine and dehydroabietylamine.

All steric isomers that comprise The compounds of this invention, or form of mixtures or pure product or pure substantially form.The compounds of this invention all can have asymmetric center on any carbon atom (comprising the substituent any carbon atom of R).Therefore, formula I compound can enantiomorph or diastereomer form or the existence of its form of mixtures.Can utilize racemic modification, enantiomorph or diastereomer as raw material in its preparation process.When preparation diastereomer or enantiomorph product, can as chromatography or fractional crystallization, separate by method commonly used.

If requirement can give the antidiabetic of structure I compound and one or more other type and/or the therapeutical agent combined utilization of one or more other type with same formulation or with independent oral dosage form form orally give or by injection.

Can be 1 with the antidiabetic of other type of the optional combined utilization of sodium dependent glucose transport protein 2 (SGLT2) inhibitor of formula I, 2,3 or more kinds of antidiabetic or antihyperglycemic agents, comprise that Drugs Promoting Insulin Secretion or insulin sensitizer or other preferably have the antidiabetic of the mechanism of action that is different from the SGLT2 inhibition, can comprise biguanides, sulfonylurea, alpha-glucosidase inhibitors, peroxisome proliferation albumen activation receptor (PPAR) Y agonist, as thiazolidinedione, fatty acid binding protein aP2 inhibitor, PPAR α/Y dual agonists, dipeptidyl peptidase 4 (DP4) inhibitor and/or fluorine fennel benzoic acid (meglitinide) and Regular Insulin and/or glucagon-like-peptide-1 (GIP-1).

Now think structure I compound and 1,2,3 or the hyperglycemia effect that produces of more kinds of other antidiabetic combined utilization stronger than using these medicines separately separately, and stronger than the hyperglycemia effect of the merging addition of these medicines generations.

Other antidiabetic drug can be oral antihyperglycemic agents, preferred biguanide, and as N1,N1-Dimethylbiguanide, phenformin or its salt, preferred Walaphage.

If described other antidiabetic is a biguanides, the so used structure I compound and the weight ratio of biguanides about 0.01: 1 to about 100: 1 scope, preferred about 0.1: 1 to about 5: 1 scope.

Other antidiabetic drug is sulfonylurea preferably, as Glyburide (being also referred to as glibenclamide), glimepiride (United States Patent (USP) 4,379, open in 785), Glipizide, gliclazide or P-607, act on other sulfonylurea or other antihyperglycemic agents of the ATP-dependency passage of β cell, preferred Glyburide and Glipizide can give them with same or independent oral dosage form.

The used structure I compound and the weight ratio of this sulfonylurea about 0.01: 1 to about 100: 1 scope, preferred about 0.2: 1 to about 10: 1 scope.

Other oral antidiabetic that can give with same or independent oral dosage form can also be an alpha-glucosidase inhibitors, as acarbose (United States Patent (USP) 4,904,769 in open) or miglitol (United States Patent (USP) 4,639,436 in open).

The used structure I compound and the weight ratio of this alpha-glucosidase inhibitors about 0.01: 1 to about 100: 1 scope, preferred about 0.5: 1 to about 50: 1 scope.

The structure I compound can with PPARY agonist combined utilization, the oral antidiabetic of described agonist such as thiazolidinedione or other insulin sensitizer (it has the insulin sensitivity effect to NIDDM patient) are as the troglitazone (Rezulin of Warner-Lambert ^_United States Patent (USP) 4,572, open in 912), the MCC-555 (United States Patent (USP) 5 of rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi, 594, open in 016), the GL-262570 of Glaxo-Welcome, englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer), isaglitazone (MIT/J﹠amp; J), JTT-501 (JPNT/P﹠amp; U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr.Reddy/NN) or YM-440 (Yamanouchi), preferably rosiglitazone (rosiglitazone) and pyrroles's row ketone.

The used structure I compound and the weight ratio of this thiazolidinedione about 0.01: 1 to about 100: 1 scope, preferred about 0.2: 1 to about 10: 1 scope.

Consumption can be less than this sulfonylurea of about 150mg and the oral antidiabetic of thiazolidinedione and structure I compound merges in single tablet.

The structure I compound also can with antihyperglycemic agents such as Regular Insulin or hyperglycemic-glycogenolytic factor auspicious peptide-1 (GLP-1), as GLP-1 (1-36) acid amides, GLP-1 (7-36) acid amides, GLP-1 (the 7-37) (United States Patent (USP) 5 of Habener, 614, open in 492, the disclosure content is attached among the present invention as a reference) and AC2993 (Amylen) and LY-315902 (Lilly) combined utilization, give by injection, nasal cavity or by device in skin or cheek.

If have N1,N1-Dimethylbiguanide, sulfonylurea (as Glyburide, glimepiride, glipyride, gliclazide, P-607 and gliclazide) and alpha-glucosidase inhibitors acarbose or miglitol (in the injectable, lung, in the cheek or orally give) in the above-described preparation, its consumption and dosage can be according to explanations among the Physician ' s Desk Reference (PDR).

If have N1,N1-Dimethylbiguanide or its salt, its consumption within the scope of about 500-2000mg/ day, this amount can with single dose or every day 1-4 time divided dose give.

If there is the thiazolidinedione antidiabetic, its consumption within the scope of about 0.01-2000mg/ day, this amount can with single dose or every day 1-4 time divided dose give.

If there is Regular Insulin in the preparation, its consumption and dosage can be according to explanations among Physician ' the s DeskReference (PDR).

If there is the GLP-1 peptide, can be according to the United States Patent (USP) 5,346,701 (TheraTech), 5,614,492 and 5,631 that is attached among the present invention as a reference, explanation in 224 is by oral cavity buccal form administration, by intranasal administration or parenterai administration.

Other antidiabetic can also be PPAR α/γ dual agonists, as AR-HO39242 (Astra/Zeneca), GW-409544 (Glaxo-Wellcome), KRP297 (Kyorin Merck) and Murakami etc. at Diabetes 47,1841-1847 (1998) " the neo-insulin sensitizing agent is as the common ligands of peroxisome proliferation-activated receptor α (PPAR α) and PPAR γ.PPAR α activation is to the metabolic effect of abnormal lipids of Zucker obese rat liver " in those disclosed antidiabetic; with and disclosure be attached among the present invention the U.S. Provisional Application 60/155 of application in 22 days September in 1999 as a reference; disclosed antidiabetic among 400 (the attorney's file LA29); its using dosage wherein is indicated as being preferred compound and is the preferred compound that uses among the present invention by the dosage that wherein proposes.

Other antidiabetic can also be the aP2 inhibitor, as the U. S. application sequence number 09/391,053 of application on September 7th, 1999 and U.S. Provisional Application 60/127,745 (attorney's file LA27 of application on April 5th, 1999 ^*) in disclosed antidiabetic, its using dosage is by the dosage that proposes among the present invention.Preferred aP2 inhibitor promptly is the preferred compound of indication in the above application.

Other antidiabetic can also be the DP4 inhibitor, as disclosed DP4 inhibitor, Hughes etc. among WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278 (PROBIODRUG), the WO99/61431 (PROBIODRUG) at Biochemistry, 38 (36), 11597-11603, disclosed NVP-DPP728A (1-[[[2-[(5-cyanopyridine-2-yl) amino in 1999] ethyl] amino] ethanoyl]-2-cyano group-(S)-tetramethyleneimine) (Novartis) (preferably), Yamada etc. are at Bioorg.﹠amp; Disclosed TSL-225 among Med.Chem.Lett.8 (1998) 1537-1540 (tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-formic acid), Ashworth etc. are at Bioorg.﹠amp; Med.Chem.Lett.6 volume, 22 phases, the dosage that disclosed 2-Cyanopyrolidine and 4-Cyanopyrolidine in 1163-1166 and the 2745-2748 page or leaf (1996), its using dosage propose in zhang offering by above reference.

The meglitinide that can choose wantonly with formula I compound combined utilization of the present invention can be repaglinide, nateglinide (Novartis) or KAD1229 (PF/Kissei), wherein preferred repaglinide.

The weight ratio of used formula ISGLT2 inhibitor and this meglitinide, PPARY agonist, PPAR α/Y dual agonists, aP2 inhibitor or DP4 inhibitor about 0.01: 1 to about 100: 1 scope, preferred about 0.2: 1 to about 10: 1 scope.

Can comprise 1 with the hypolipidemic or the lipid lowering agent of the optional combined utilization of formula I compound of the present invention; 2; 3 or more kinds of microsomal triglyceride transfer protein (MTP) inhibitor; hydroxy-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitor; inhibitor for squalene synthetic enzyme; Carboxymethylcellulose (fibric acid) derivative; acyl-CoA cholesterol transferring enzyme (ACAT) inhibitor; lipoxygenase inhibitor; cholesterol absorption inhibitor; ileum Na+/bile acide cotransporter inhibitor; low-density lipoprotein (LDL) receptor active positive regulator; bile acid chelating agent and/or nicotinic acid and derivative thereof.

The used MTP inhibitor of the present invention comprises United States Patent (USP) 5,595,872, United States Patent (USP) 5,739,135, United States Patent (USP) 5,712,279, United States Patent (USP) 5,760, and 246, United States Patent (USP) 5,827,875, United States Patent (USP) 5,8 85, on October 20th, 983 and 1998, the U. S. application sequence number 09/175,180 of application now was a United States Patent (USP) 5,962, disclosed MTP inhibitor in 440, preferred L TP inhibitor promptly are disclosed various preferred MIP inhibitor in above each patent and the application.

More than all United States Patent (USP)s and application all be attached among the present invention as a reference.

The most preferably MTP inhibitor that uses among the present invention comprises United States Patent (USP) 5,739,135, United States Patent (USP) 5,712,279 and United States Patent (USP) 5,760,246 in the preferred MTP inhibitor that proposes.

Most preferred MTP inhibitor is 9-[4-[4-[[2-(2,2, a 2-trifluoro ethoxy) benzoyl] amino]-piperidino] butyl]-N-(2,2, the 2-trifluoro ethoxy)-9H-fluorenes-9-methane amide

Hypolipidemic can be a HMG CoA reductase inhibitor, and it includes, but are not limited to as United States Patent (USP) 3,983, disclosed mevastatin and related compound thereof in 140, as United States Patent (USP) 4,231, disclosed lovastatin (Mei Shulin mevinoline) and related compound thereof in 938, as United States Patent (USP) 4,346, disclosed Pravastatin and related compound thereof in 227, as United States Patent (USP) 4,448,784 and 4, disclosed Simvastatin and related compound thereof in 450,171.Other HMG CoA reductase inhibitor of available comprises among the present invention, but be not limited to United States Patent (USP) 5,354, disclosed fluvastatin in 772, United States Patent (USP) 5,006,530 and 5,177, disclosed cerivastatin in 080, United States Patent (USP) 4,681,893,5,273,995,5,385,929 and 5,686, disclosed atorvastatin in 104, United States Patent (USP) 5,011, disclosed atavastatin in 930 (nisvastatin of Nissan/Sankyo (NK-104)), United States Patent (USP) 5,260, disclosed Shionogi-Astra/Zeneca visastatin (ZD-4522) and United States Patent (USP) 5 in 440,753, disclosed relevant statin compound in 675, United States Patent (USP) 4,613, in 610 disclosed 3,5-dihydroxyl-3 methylvaleric acid lactone derivatives pyrazole analogs, among the PCT application WO 86/03488 disclosed 3, the indenes analogue of 5-dihydroxyl-3 methylvaleric acid lactone derivatives, United States Patent (USP) 4,647, disclosed 6-[2-in 576 (replacement-pyrroles-1-yl)-alkyl] pyran-2-one and derivative thereof, the SC-45355 of Searle (a kind of glutaric acid derivatives of replacement) dichloro acetic acid ester, among the PCT application WO86/07054 disclosed 3, the imidazoles analogue of 5-dihydroxyl-3 methylvaleric acid lactone, French Patent 2,596, disclosed 3-carboxyl-2-hydroxyl-pentane phosphonate derivative in 393, disclosed 2 in the european patent application 0221025, the 3-disubstituted pyrroles, furans and thiophene derivant, United States Patent (USP) 4,686, in 237 disclosed 3, the naphthyl analogue of 5-dihydroxyl-3 methylvaleric acid lactone, for example United States Patent (USP) 4,499, disclosed octahydro naphthalene in 289, european patent application 0,142, the ketone group analogue of disclosed Mei Shulin (lovastatin) and United States Patent (USP) 5,506,219 and 5 among 146 A2, disclosed quinoline and pyridine derivate in 691,322.

In addition, openly be applicable to the phosphinic acid compounds that can be used for suppressing HMG CoA reductase enzyme that uses among the present invention among the GB 2205837.

Be applicable to that the inhibitor for squalene synthetic enzyme that uses among the present invention includes, but are not limited to United States Patent (USP) 5,712; disclosed α-phosphono-sulphonate in 396; Biller etc. are at J.Med.Chem., and 1988,31 roll up; 10 phases, those disclosed inhibitor among the 1869-1871; comprise isoprenoid (phosphinyl methyl) phosphonic acid ester and other known inhibitor for squalene synthetic enzyme, as United States Patent (USP) 4; 871; 721 and 4,924,024 and Biller; S.A.; Neuenschwander, K., Ponpipom; M.M.; and Poulter, C.D. is at Current Pharmaceutical Design; 2, those disclosed inhibitor among the 1-40 (1996).

In addition, be applicable to that other inhibitor for squalene synthetic enzyme that uses among the present invention comprises P.Ortiz de Montellano etc. at J.Med.Chem., 1977, 20, among the 243-249 disclosed terpenoid pyrophosphate, Corey and Volante at J.Am.Chem.Soc., 1976,98, disclosed bisphosphate farnesyl ester analogs among the 1291-1293 AWith preceding squalene pyrophosphate (PSQ-PP) analogue, McClard, R.W. etc. are at J.A.C.S., and 1987, 109, the phosphinyl phosphonic acid ester and the Capson of report in 5544, T.L., PhD dissertation, June, 1987, Dept.Med.Chem.U of Utah, Abstract, Table of Contents, pp 16,17,40-43, the cyclopropanes of reporting among the 48-51.

Be applicable to that other hypolipidemic that uses among the present invention comprises, but be not limited to fibric acid derivative, as fenofibrate, Ji Feibeite, clofibrate, bezafibrate, Win-35833, S-8527 etc., United States Patent (USP) 3,674, disclosed probucol and related compound thereof, preferred probucol and Ji Feibeite in 836, bile acid chelating agent is as Colestyramine, colestipol and DEAE-Sephadex (Secholex ^_, Policexide ^_) and lipostabil (Phone-Poulenc), Eisai E-5050 (ethanolamine derivant that a kind of N-replaces), imanixil (HOE-402), tetrahydrochysene lipstatin (THF), istigmastanyl phosphatidylcholine (SPC, Roche), amino cyclodextrin (Tanabe Seioku), Ajinomoto AJ-814 (azulene derivatives), melinamide (Sumitomo), Sandoz 58-035, American CyanamidCL-277,082 and CL-283,546 (2-substituted carbamide derivatives), nicotinic acid, acipimox, Acifran, Xin Meisu, para-aminosalicylic acid, acetylsalicylic acid, as United States Patent (USP) 4,759, disclosed many (diallyl methylamine) derivative in 923, quaternary ammonium many (chlorination diallyl dimethylammoniums) and as United States Patent (USP) 4, the medicine of disclosed ionene and other reduction plasma cholesterol in 027,009.

Other hypolipidemic can be the ACAT inhibitor, as Drugs of the Futhre 24, and 9-15 (1999), (avasimibe (Avasimibe)); Nicolosi etc. Atherosclerosis (Shannon, Irel). (1998), 137 (1), the area of hamster aorta fatty streaks district " the ACAT inhibitor, C1-1101 can suppress effectively and disappear " of 77-85; Ghiselli, Giancarlo, in Cardiovasc.Drug Rev. (1998), 16 (1), 16-30 " the pharmacological profile type of FCE 27677: a kind of new ACAT inhibitor, its have by selectivity suppress to contain the efficient hypolipidemic activity that the liver secretion of the lipoprotein of ApoB100 mediates "; Smith, C. etc. be in Bioorg.Med.Chem.Lett. (1996), and 6 (1), 47-50 " RP73163: but a kind of alkyl sulphinyl of biological utilisation-diphenyl-imidazole ACAT inhibitor "; Editors such as Krause: Ruffolo, RobenR., " ACAT inhibitor, the active physiological mechanisms of reducing blood-fat and atherosclerosis in experimental animal " of Jr.; Hollinger, Mannfred A., at CRC, Boca Raton, the Inflammation:Mediators Pathways (1995) that Fla publishes, 173-98; Sliskovic etc. are at Curr, Med.Chem. (1994), 1 (3), " the ACAT inhibitor: potential antiatherosclerotic " of 204-25; Stout etc. are in Chemtracts:Org.Chem. (1995), 8 (6), 359-62 " acyl group-CoA inhibitor: cholesterol O-acyltransferase (ACAT) is as hypocholesterolemic agents.6. first has the active water-soluble ACAT inhibitor of the lipid of adjusting.Acyl group-CoA inhibitor: cholesterol acyltransferase (ACAT).7. a series of progress with N-phenyl-N '-[(the 1-benzyl ring amyl group) methyl] urea that strengthens the active replacement of hypercholesterolemia " etc. in disclosed ACAT inhibitor or TS-962 (Taisho Pharmaceutical Co.Ltd).

Hypolipidemic can be the positive regulator of LD2 receptor active, as MD-700 (TaishoPharmaceutical Co.Ltd) and/or LY295427 (Eli Lilllv).

Hypolipidemic can be a cholesterol absorption inhibitor, SCH48461 and the Atherosclerosis 115 of preferred Schering-Plough, 45-63 (1995) and J.Med.Chem., 41,973 (1998) middle those disclosed inhibitor.

Hypolipidemic can be ileum Na+/bile acide cotransporter inhibitor, as Drugsof the Future, and 24, those disclosed inhibitor among the 425-430 (1999).

Preferred hypolipidemic is Pravastatin, lovastatin, partly cuts down his spit of fland, Zarator (atorvastatin), fluvastatin, Cerivastatin (cerivastatin), atavastatin and ZD-4522.

Above-mentioned United States Patent (USP) all is attached among the present invention and carries out according to explanation in Physician ' s Desk Reference and/or the above-mentioned patent as reference used amount and dosage.

The weight ratio of used formula I compound of the present invention and hypolipidemic (if exist) about 500: 1 to about 1: 500 scope, preferred about 100: 1 to about 1: 100 scope.

Dosage must carefully be regulated according to patient's age, body weight and illness and route of administration, formulation and scheme and desired effect.

The dosage of hypolipidemic and preparation are disclosed dosage and preparation in various patent discussed above and the application.

Dosage of other used hypolipidemic (if application) and preparation are according to the dosage and the preparation that propose among the latest edition Physician ' s Desk Reference.

For oral administration, adopt about 0.01-500mg/kg, the MTP inhibitor of preferably about 0.1-100mg/kg dosage range is taken for 1-4 time every day, can obtain satisfactory therapeutic effects.

Preferred oral dosage form (as tablet or capsule) contains the 1-500mg that has an appointment, preferably about 2-400mg, and the more preferably MTP inhibitor of 5-250mg dosage range is taken for 1-4 time every day.

For oral administration, adopt the dosage that proposes among the Physician ' s Desk Reference, about 1-2000mg, the HMG CoA reductase inhibitor of preferred about 4-200mg dosage range, as Pravastatin, lovastatin, Simvastatin, atorvastatin, fluvastatin or cerivastatin, can obtain satisfactory therapeutic effects.

The using dosage of spiny dogfish synthetase inhibitors can be in the scope of about 10-2000mg, preferably the scope of about 25-200mg.

Preferred oral dosage form (as tablet or capsule) contains the 0.1-100mg that has an appointment, preferably about 5-80mg, more preferably from about the HMG CoA reductase inhibitor of 10-40mg dosage.

Preferred oral dosage form (as tablet or capsule) contains the 10-500mg that has an appointment, the spiny dogfish synthetase inhibitors of preferably about 25-200mg dosage.

Other hypolipidemic can also be a lipoxygenase inhibitor, comprise 15-lipoxidase (15-LO) inhibitor, as disclosed benzimidizole derivatives among the WO 97/12615, disclosed 15-LO inhibitor among the WO97/12613, disclosed isothiazolone among the WO 96/38144, Sendobry etc. are at Brit.J.Pharmacology (1997) 120, " atherosclerosis of bringing out with the highly selective 15-lipoxygenase inhibitor reduction rabbit diet that lacks obvious antioxidation property " of 1199-1206 and Cornicelli etc. are at Current Pharmaceutical Design, 1999,5, disclosed 15-LO inhibitor in 11-20 " 15-lipoxidase and inhibition thereof: a kind of new treatment target of vascular disease ".

Formula I compound can use in same formulation with hypolipidemic, perhaps can take simultaneously with the form of oral dosage form separately.

Can with the composition of above explanation by above explanation with formulation, single give or with every day 1-4 time divided dose form give.Can advise that the patient runs the beginning jointly with low dose group, increase to the high dosage combination gradually.

Preferred hypolipidemic is Pravastatin, Simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.

Can be 1,2,3 or more kinds of antiobesity agent with the therapeutical agent of other type of the optional combined utilization of the SGLT2 inhibitor of formula I, comprise β ₃2-adrenergic agonist components, lipase inhibitor, serotonin (and Dopamine HCL) absorption inhibitor, thryoid receptor β medicine and/or appetite suppressant.

Can choose the β of combined utilization with formula I compound wantonly ₃2-adrenergic agonist components can be AJ9677 (Takeda/Dainippon), L750355 (Merck) or CP331648 (Pfizer) or United States Patent (USP) 5,541,204,5,770,615,5,491,134,5,776, disclosed other known β in 983 and 5,488,064 ₃Agonist, preferred AJ9677, L750355 and CP331648.

Can be orlistat or ATL-962 (Alizyme) with the lipase inhibitor of the optional combined utilization of formula I compound, preferred orlistat.

Can be sibutramine, topiramate (Johnson ﹠amp with serotonin (and Dopamine HCL) reuptake inhibithors of the optional combined utilization of formula I compound; Johnson) or Dapiclermin (axokine) (Regeneron), preferred sibutramine and topiramate.

Can choose the thryoid receptor beta compounds of uniting use with formula I compound wantonly can be disclosed ligands for thyroid receptor among WO97/21993 (U.Cal SF), W0 99/00353 (KaroBio) and the GB 9/284425 (KaroBio), the compound of wherein preferred KaroBio application.

Can choose the appetite suppressant of uniting use with formula I compound wantonly can be Dextrofenfluramine, phentermine, Phenylpropanolamine or Mazindol, wherein preferred Dextrofenfluramine.

The various antiobesity agents and the formula I compound of above explanation can be used with same formulation or with different dosage form, its dosage and dosage regimen can be determined according to this area generalized case or according to PDR.

When utilization the inventive method treatment diabetes and relative disease, adopt medicinal compositions, said composition to comprise structure I compound, comprise or do not comprise the therapeutical agent of other antidiabetic and/or lipidemia agent and/or other type in conjunction with pharmaceutically acceptable carrier or thinner.The medicinal additive that can use solid commonly used or liquid vehicle or thinner and be suitable for the administering mode type that requires as pharmaceutically acceptable carrier, vehicle, tackiness agent etc., is made medicinal compositions.But by oral route, as with tablet, capsule, microspheres agent, granule or powder form, give Mammals (comprising people, monkey, dog etc.) described compound, perhaps with the injection form, give by parenteral route, perhaps by giving in the nose or through skin patch form.General solid preparation comprises the formula I compound of about 10-500mg.Adult's dosage is preferably at 10-2000mg/ between day, and this dosage can give by every day single dose or every day 1-4 time divided dose form.

General injection can by aseptic insert in the phial 250mg structure I compound, aseptic lyophilize seals preparation then.Treat the time spent, content in the phial and 2mL physiological saline are mixed and made into the injection use.

The SGLT2 inhibitor activity of The compounds of this invention can be by adopting following mensuration system to measure.

The SGLT2 determination of activity

Adopt standard molecular biological technique, by reverse transcription and the amplification of people's kidney mRNA, the mRNA sequence (GenBank #M95549) of human cloning SGLT2.CDNA sequence stable transfection in Chinese hamster ovary celI, and is illustrated according to (1994) such as Ryan substantially, the clone is carried out the SGLT2 determination of activity.Substantially according to explanation and the following change of Ryan etc., to carry out the active assessment that suppresses of SGLT2 through the clone of clonal selection.In 96 orifice plates, cell is cultivated 2-4 day in every hole F-12 nutrient mixing liquid (Ham ' s F-12), 10% foetal calf serum, 300ug/ml Geneticin and penicillin-Streptomycin sulphate, until reaching 75000 or 30000 cells.After converging, with cell 10mM Hepes/Tris, pH 7.4,137mM N-methyl D-glucosamine, 5.4mMKCl, 2.8mM CaCl ₂, 1.2mM MgSO ₄Wash 2 times.Under 37 ℃, at 10mMHepes/Tris, pH 7.4 then, 137mM NaCl, 5.4mM KCl, 2.8mM CaCl ₂, 1.2mMMgSO ₄In, with cell and 10 μ M[ ¹⁴C] AMG and 10 μ M inhibitor (whole DMSO=0.5%) hatched 1.5 hours.With the ice-cold 1X PBS quencher absorption measurement that contains the 0.5mM phlorizin, use the 0.1%NaOH lysing cell then.Add the MicroScint scintillation solution, with cell jolting 1 hour, use then the TopCount scintillometer to [ ¹⁴C] AMG is quantitative.With having or not having NaCl and carry out blank.For measuring ED ₅₀Value in the appropriate responsive scope, in the log interval, adopts 10 inhibitor concentration, and the different culture plate data of three culture plates of the same form is averaged.

Ryan Mj, Johnson G, Kirk J, Fuerstenberg SM, Zager RA and Torok-Storb be immortalized proximal tubule epithelial cell line fromnormal adult human kidney (deriving from the immortalization proximal tubule epithelial cell line of normal adult kidney) B.1994.HK-2:an.idney International 45：48-57。

Following work embodiment represents the preferred embodiments of the invention.Unless otherwise indicated, all temperature are all used and degree centigrade are represented.

Embodiment 1

A.4-methyl-2 '-hydroxy diphenyl methyl alcohol

Under Ar, in the 500ml round-bottomed flask that 100mL THF is housed, add commercially available 1M p-methylphenyl magnesium bromide/Et ₂O (100mL, 10mmol).Then, in 2 hours, branch quarter dropping salicylic aldehyde (4.9g, 40.3mmol).After 20 minutes, after the HPLC analysis shows that this aldehyde is exhausted, drip the saturated NH of 26ml immediately ₄Cl/H ₂This reactant of O quencher obtains white paste.In this suspension, add the water of 200mL PhMe and capacity, stir.Inclining organic layer, and this white paste is ground a moment with 1: 1 THF/PhMe.Inclining organic layer, concentrates the organic layer that merges with rotatory evaporator, obtains 9.7g crude product 4-methyl-2 '-hydroxy diphenyl methyl alcohol.

B.2-(4 '-methyl-benzyl) phenol

In the 175mL MeOH solution of part A crude product 4-methyl-2 '-hydroxy diphenyl methyl alcohol (9.7g, amount is no more than 40mmol), add 0.59g 10%Pd/C and 1.75mLTFA.At 1atm H ₂Down, suspension was stirred 40 hours,, concentrate crude product 2-(4 '-methyl-benzyl) phenol that obtains 8.6g oily matter by diatomite filtration.

With 2-(4 '-methyl-benzyl) phenol (8.6g, amount is no more than 37mmol), 2 of part B, 6-di-t-butyl-4-picoline (10.6g; 52mmol), 2,3,4; 6-four-O-ethanoyl-α-D-glucopyranosyl bromine (17.5g, 270mL CH 43mmol) ₂Cl ₂Mixed solution is stirred to homogeneous phase, is cooled to 0 ℃ then.In this cold soln, add AgOTf (12.2g, 47mmol) after, this reactant was stirred 1 hour, and then adds 2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromine (7.6g, 18mmol) and AgOTf (6.5g, 25mmol).Need other 100mL CH ₂Cl ₂Dilute this suspension, to keep stirring.After 30 minutes, this suspension is directly packed on the silicagel column, begin with 25%EtOAc/ hexane wash-out.At first wash-out is nonconforming a small amount of α end group isomerized products, and then the 25-35%EtOAc/ hexane with the increase ratio is an eluent, obtains desired title β-O-glucoside tetraacetate.After concentrating, by adding hexane, the crude product that will be dissolved in a small amount of EtOAc brings out crystallization.Obtain the desired pure title beta isomer of common 8.25g and about 3g impurity.

To portion C compound (8.25g, 35mL CH 15mmol) ₂Cl ₂In the solution, add MeOH (200mL), then add the aqueous solution of 0.7mL 1N NaOH.After 2 hours, finish, adopt rotatory evaporator to remove volatile matter by the definite reaction of HPLC.Residue is dissolved in 1: 10: 10 H ₂O/CH ₂Cl ₂In/MeOH the mixed solution (42mL), use CH ₂Cl ₂(400mL) dilution is on the silicagel column of then packing into.Use 5-7%MeOH/CH ₂Cl ₂Wash-out, remove volatile matter after, separate to obtain desired product (5.68g), be white solid.

¹H NMR (400MHz, CD ₃OD) δ 7.15-7.08 (m, 4H), 7.05 (m, 3H), 6.91 (m, 1H), 4.39 (d, 1H cover), 4.04 (d, 1H, J=14Hz), 3.95 (d, 1H, J=14Hz), 3.88 (d, 1H, J=12Hz), 3.68 (dd, 1H, J=12,3Hz), 3.52-3.36 (m, 4H), 2.27 (s, 3H).

HPLC retention time: 6.88min, Zorbax C-184.6 * 75mm, 2.5mL/min detects wavelength 220nm, and the 8min gradient contains 0-100%B, keeps 3min 100%B.Solvent orange 2 A: 10%MeOH/H ₂O+0.2%H ₃PO ₄Solvent B:90%MeOH/H ₂O+0.2%H ₃PO ₄

C ₂₀H ₂₄O ₆LC-MS (M+Na) analytical calculation value 383.

Embodiment 2

A.2-(4 '-Ethylbenzyl) phenol

Under Ar, (144mg, (284mg is in PhMe 3mmol) (15mL) solution 3.6mmol) to be added drop-wise to the phenol of stirring with 60%NaH/ Dormant oils dispersion liquid.After 10 minutes, (1.23g, PhMe 5.3mmol) (2mL) solution is then under 80 ℃, with reactant heating 6 hours to ethylbenzyl chloride in adding.After the cooling, remove volatile matter, residue is dissolved among the 15mLMeOH with rotatory evaporator.With hexane extraction 4 times of this MeOH solution, concentrate then.The residue that obtains is dissolved in 1: 1 EtOAc/H ₂Among the O (100mL),, separate two-phase with pH regulator to 5.Through Na ₂SO ₄Drying is removed EtOAc, obtains 390mg crude product title compound 2-(4 '-Ethylbenzyl) phenol.Preparation property HPLC obtains the pure 2-of 275mg (4 '-Ethylbenzyl) phenol.

Under 20 ℃, with 2-(4 '-Ethylbenzyl) phenol (212mg, 1mmol), 2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromine (822mg, 2mmol) and Ag ₂(232mg, 4mL lutidine suspension 2mmol) stirred 14 hours O.HPLC detects and to finish 80% conversion, adds 2,3,4 again, and 6-four-O-ethanoyl-α-D-glucopyranosyl bromine (411mg, 1mmol) and Ag ₂(116mg 1mmol), proceeds 24 hours with reactant to O.Add entry (5mL) and 1N aq.NaOH (2mL) then, this suspension was stirred 16 hours.Reaction mixture is extracted 2 times with EtOAc.With the EtOAc extracting solution through Na ₂SO ₄Drying concentrates then.The residue that obtains obtains the 8.7mg end product through preparation property HPLC purifying.

¹H NMR (400MHz, CD ₃OD) δ 7.15 (m, 4H), 7.08-7.01 (m, 3H), 6.91 (m, 1H), 4.91 (d, 1H cover), 4.08 (d, 1H, J=14Hz), 3.95 (d, 1H, J=14Hz), 3.88 (d, 1H, J=12Hz), 3.68 (dd, 1H, J=12,3Hz), 3.53-3.37 (m, 4H), 2.57 (q, 2H, J=7Hz), 1.18 (t, 3H, J=7Hz).

HPLC retention time: 7.32min, Zorbax C-18 4.6 * 75mm, 2.5mL/min detects wavelength 220nm, and the 8min gradient contains 0-100%B, keeps 3min 100%B.Solvent orange 2 A: 10%MeOH/H ₂O+0.2%H ₃PO ₄Solvent B:90%MeOH/H ₂O+0.2%H ₃PO ₄

C ₂₂H ₂₆O ₆LC-MS (M+Na) analytical calculation value 397.

Embodiment 3

A.2-benzyloxy-4 '-methyldiphenyl base ether

With 2-benzyloxy phenol (5g, 2.49mmol), Cu (OAc) ₂(452mg, 2.49mmol), p-methylphenyl boric acid (339mg, 2.49mmol) and the activation 4_ molecular sieve (10g) CH ₂Cl ₂(8mL) mixed solution stirred for several minute adds Et then ₃N (1.26g, 12.5mmol), then add pyridine (0.99g, 12.5mmol).Stir after 20 hours, reactant by diatomite filtration, is used CH ₂Cl ₂Washing.Concentrated filtrate, residue with 4%EtOAc/ hexane wash-out, obtain the desired title compound 2-of 280mg (39%) benzyloxy-4 '-methyldiphenyl base ether through silica gel column chromatography.

B.2-hydroxyl-4 '-methyldiphenyl base ether

At 1atm H ₂Down, (280mg, (50mL) solution of MeOH 0.96mmol) and Pd/C (30mg) stir and spend the night with the part A compound.Reactant by diatomite filtration, is used MeOH and CH ₂Cl ₂Washing in turn.Removing desolvates obtains 190mg title compound 2-hydroxyl-4 '-methyldiphenyl base ether.

Under 65 ℃, will contain part B compound (94mg, 0.47mmol), 2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromine (185mg, 0.45mmol) and Ag ₂(62mg, 1.0mL lutidine suspension 0.27mmol) stirred 19 hours O.When the HPLC analytical reaction finish 50%, add 2,3,4 again, 6-four-O-ethanoyl-α-D-glucopyranosyl bromine (185mg, 0.45mmol) and Ag ₂(62mg 0.27mmol), proceeds 3 hours with reactant to O.After the cooling, add 1N HCl (25mL), extract 3 times (cumulative volume 75mL) with EtOAc then.With organic extracting solution water, the aq.NaHCO that merges ₃With the salt water washing, through MgSO ₄Dry.After the solvent removed in vacuo, obtain the 50mg crude product.Without purifying, this material is being contained LiOH (4.7mg, 1: 2: 3 H 0.17mmol) ₂Stir among the O/THF/MeOH (1mL) and spend the night.Remove volatile matter, residue is through preparation property HPLC purifying, with YMC S5 C18 reversed-phase column 10min gradient elution (30%-90%MeOH/H ₂O), obtain the final O-glucoside of 26mg after the lyophilize.

¹H NMR(400MHz，CD ₃OD)δ2.29(s，3H)，3.34-3.42(m，4H)，3.67(dd，1H，J＝4.8，11.3Hz)，3.85(dd，1H，J＝2.2，11.9Hz)，4.95(d，1H，J＝7.0Hz)，6.82-7.29(m，8H)。

HPLC retention time: 6.47min, purity 97%, Zorbax C-18 4.6 * 75mm, 2.5mL/min detects wavelength 220nm, and the 8min gradient contains 0-100%B, keeps 3min 100%B.Solvent orange 2 A: 10%MeOH/H ₂O+0.2%H ₃PO ₄Solvent B:90%MeOH/H ₂O+0.2%H ₃PO ₄

C ₁₉H ₂₂O ₇The low MS analytical calculation value of differentiating: [M+Na]=385, [M+NH4]=380, [2M+NH4]=742, [M-H]=361, [2M-H]=723.

Embodiment 4

Under 20 ℃, with the 2-nitrophenols (1.67g, 12mmol), 2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromine (4.5g, 10.9mmol) and Ag ₂(1.6g, 20mL lutidine suspension 7.1mmol) stirred 19 hours O.With reactant 250mL CH ₂Cl ₂Diatomite filtration is passed through in dilution.Use CH again ₂Cl ₂Behind the washing diatomite, concentrate the organic moiety that merges, obtain yellow residue.Grind (4X) with MeOH and dissolve most of impurity, obtain 4.15g and require title compound 2-nitrophenyl-O-glucoside.

At 1atm H ₂Down, will be partially soluble in the 35mL 2: 2 that contains 0.2g 10%Pd/C: the part A crude product compound (2g) among the 3THF/DCE/MeOH stirred 16 hours, passed through diatomite filtration then.Filtrate (the MeOH washing lotion that comprises diatomite layer) is concentrated, obtain the adjacent anilino of 1.8g title compound-O-glucoside.

With part B compound (100mg, 0.23mmol), Pd (OAc) ₂(2.5mg, 0.01mmol), (0.8mg, 0.0014mmol) (51mg 0.23mmol) is containing 1 Et to BINAP with the trifluoromethanesulfonic acid phenyl ester ₃Stirred 5 minutes in the PhMe of N (1mL) mixed solution, add Cs then ₂CO ₃(103mg, 0.32mmol).Be heated to 102 ℃, this bright yellow solution reddens.After 15 hours, HPLC shows new peak on the residue.Attempt by adding other reactive component so that its conversion, but success.After being cooled to 20 ℃,, pass through diatomite filtration with EtOAc diluting reaction thing.Concentrated filtrate, residue with 3: 7 EtOAc/ hexane wash-outs, obtain the desired title product of 10mg through silica gel column chromatography.

Containing LiOH (1mg, 1: 2: 3 H 0.023mmol) ₂Among the O/THF/MeOH (0.6mL), (10mg 0.019mmol) stirs and spends the night with the tetraacetate of portion C.With among the 1N HCl and after remove volatile matter.Residue is used 10min gradient elution (30%-90%MeOH/H through preparation property HPLC purifying on YMC S5 C18 reversed-phase column ₂O), obtain the final glucoside of 3mg after the lyophilize.

¹H NMR(500MHz，CD ₃OD)δ3.37-3.52(m，4H)，3.72(dd，1H，J＝5Hz)，3.89(dd，1H，J＝2Hz)，4.74(d，1H，J＝8Hz)，6.77-7.28(m，9H)。

HPLC retention time: 6.2min, 100% purity, Zorbax C-18 4.6 * 75mm, 2.5mL/min detects wavelength 220nm, and the 8min gradient contains 0-100%B, keeps 3min 100%B.Solvent orange 2 A: 10%MeOH/H ₂O+0.2%H ₃PO ₄Solvent B:90%MeOH/H ₂O+0.2%H ₃PO ₄

C ₁₈H ₂₂NO ₆The low MS[M+H that differentiates] analytical calculation value=348.

Embodiment 5

A.2-hydroxyl-4 '-diphenyl sulfide

With 60%NaH/ mineral oil (260mg 6.5mmol) with pentane washing 2 times, then under 0 ℃, Ar, stirs down it is suspended among the THF (10mL), add purified adjacent bromophenol (500 μ L, 746mg, 4.3mmol).After stirring 1 hour under 20 ℃, solution is cooled to-78 ℃, adding 1.28M t-BuLi/ hexane (3.7mL, 4.7mmol).After 10 minutes, add 3mL di-p-tolyl two sulphur (1.06g, THF solution 4.3mmol).Reactant was stirred 10 minutes, be warmed to 0 ℃ then, under this temperature, kept 1 hour.Add the saturated NH of 2mL ₄Cl aqueous solution quencher reactant is then with 150mL EtOAc dilution.EtOAc is used saturated NH mutually ₄The Cl solution washing is through MgSO ₄Drying concentrates and obtains yellow oil (910mg).Silica gel column chromatography obtains 2-hydroxyl-4 '-diphenyl sulfide (555mg) with 5: 1 hexane/EtOAc wash-outs, is clarification oily matter.

With the part A compound (300mg, 1.39mmol), 2,6-di-t-butyl-4-picoline (3 87mg, 1.88mmol), 2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromine (661mg, 9mL CH 1.61mmol) ₂Cl ₂Solution stirring is cooled to 0 ℃ then to homogeneous phase.In this cold soln, add AgOTf (456mg, 1.88mmol) after, this reactant was stirred 2.5 hours, and then adds 2,3,4,6-four-O-ethanoyl-α-D-glucopyranosyl bromine (274mg, 0.66mmol) and AgOTf (157g, 0.61mmol).After 2 hours, this suspension is directly packed on the silicagel column, begin with 1: 2 EtOAc/ hexane wash-out.At first wash-out is nonconforming a small amount of α anomer (99mg), then is desired title compound four-acetoxyl group-β-O-glucoside (660mg).

Containing LiOH (40mg, 1: 2: 3 H 1mmol) ₂Among the O/THF/MeOH (9.6mL), (525mg 0.96mmol) stirred 6 hours with the tetraacetate of part B.With among the 1N HCl and after remove volatile matter.20% residue is used 10min gradient elution (50%-90%MeOH/H through preparation property HPLC purifying on YMC S5 C18 reversed-phase column ₂O), obtain the final glucoside of 24mg after the lyophilize.

¹H NMR(400MHz，CD ₃OD)δ7.29(m，2H)，7.18(m，4H)，6.88(m，2H)，4.98(d，1H，J＝7.0Hz)，3.88(m，1H)，3.70(dd，1H，J＝4.8，11.9Hz)，3.43(m，4H)，2.34(s，3H)。

HPLC retention time: 6.85min; HI=100%; YMC S3 post ODS 4.6 * 50mm, 2.5mL/min detects wavelength 220nm, and 8min gradient 0-100%B keeps 5min 100%B.Solvent orange 2 A: 10%MeOH/H ₂O+0.2%H ₃PO ₄Solvent B:90%MeOH/H ₂O+0.2%H ₃PO ₄

C ₁₉H ₂₂O ₆S LC-MS analytical calculation value: [M+H] 379, [M+Na] 401, [2M+Na] 779.

Embodiment 6-99

Adopt the similar method of embodiment 1-5, the The compounds of this invention in the preparation following table.

^*(R ⁶=H, unless otherwise indicated)

The embodiment numbering	A	R ¹	R ²	R ³	R ⁴	R ^5*	MS or LC/MS (M+H) ⁺
The embodiment numbering	A	R ¹	R ²	R ³	R ⁴	R ^5*	MS or LC/MS (M+H) ⁺	6	CH ₂	H	H	H	H	H	347
7	CH ₂	H	H	H	H	2-HO	363	6	CH ₂	H	H	H	H	H	347
7	CH ₂	H	H	H	H	2-HO	363	8	CH ₂	H	H	H	H	4-MeO	377
9	CH ₂	H	H	H	H	4-tBu	403	8	CH ₂	H	H	H	H	4-MeO	377
9	CH ₂	H	H	H	H	4-tBu	403	10	CH ₂	H	H	H	H	4-MeS	393
11	CH ₂	H	H	H	H	4-Ph	423	10	CH ₂	H	H	H	H	4-MeS	393
11	CH ₂	H	H	H	H	4-Ph	423	12	CH ₂	H	H	H	H	4-BnO	453
13	CH ₂	H	H	H	H	4-iPr	389	12	CH ₂	H	H	H	H	4-BnO	453
13	CH ₂	H	H	H	H	4-iPr	389	14	CH ₂	H	H	H	H	4-Cl	381
15	CH ₂	H	H	H	H	4-MeSO ₂	425	14	CH ₂	H	H	H	H	4-Cl	381
15	CH ₂	H	H	H	H	4-MeSO ₂	425	16	CH ₂	H	H	H	H	4-CF ₃	415
17	CH ₂	H	H	H	H	4-CF ₃O	431	16	CH ₂	H	H	H	H	4-CF ₃	415
17	CH ₂	H	H	H	H	4-CF ₃O	431	18	CH ₂	H	H	H	H	4-OCH ₂CO ₂H	426
19	CH ₂	H	H	H	H	4-OCH ₂CO ₂Me	435	18	CH ₂	H	H	H	H	4-OCH ₂CO ₂H	426
19	CH ₂	H	H	H	H	4-OCH ₂CO ₂Me	435	20	CH ₂	H	H	H	H	4-OCH ₂CONEt ₂	476
21	CH ₂	H	H	H	H	4-OCH ₂CH ₂NMe ₂	434	20	CH ₂	H	H	H	H	4-OCH ₂CONEt ₂	476

22	CH ₂	H	H	H	H	The 4-styryl	449
22	CH ₂	H	H	H	H	The 4-styryl	449	23	CH ₂	H	H	H	H	3-Me	361
24	CH ₂	H	H	H	H	3-MeO	377	23	CH ₂	H	H	H	H	3-Me	361
24	CH ₂	H	H	H	H	3-MeO	377	25	CH ₂	H	H	H	H	2-MeO	377
26	CH ₂	H	H	H	H	2-Et	375	25	CH ₂	H	H	H	H	2-MeO	377
26	CH ₂	H	H	H	H	2-Et	375	27	CH ₂	H	H	H	H	2，4-Me ₂	375
28	CH ₂	H	H	H	H	3-Cl，4-Me	394	27	CH ₂	H	H	H	H	2，4-Me ₂	375
28	CH ₂	H	H	H	H	3-Cl，4-Me	394	29	CH ₂	H	H	H	H	3，4-OCH ₂O	391
30	CH ₂	Cl	H	H	H	H	381	29	CH ₂	H	H	H	H	3，4-OCH ₂O	391
30	CH ₂	Cl	H	H	H	H	381	31	CH ₂	Me	H	H	H	H	361
32	CH ₂	H	Me	H	H	H	361	31	CH ₂	Me	H	H	H	H	361
32	CH ₂	H	Me	H	H	H	361	33	CH ₂	H	F	H	H	H	365
34	CH ₂	H	Cl	H	H	H	381	33	CH ₂	H	F	H	H	H	365
34	CH ₂	H	Cl	H	H	H	381	35	CH ₂	H	(P- MeBn)	H	H	H	465
36	CH ₂	H	Cl	H	H	2-HO，5-Cl	431	35	CH ₂	H	(P- MeBn)	H	H	H	465
36	CH ₂	H	Cl	H	H	2-HO，5-Cl	431	37	CH ₂	H	Cl	H	Br	H	459
38	CH ₂	H	Br	H	Br	H	503	37	CH ₂	H	Cl	H	Br	H	459
38	CH ₂	H	Br	H	Br	H	503	39	CH ₂	H	(1, the new hexyl of 1-dimethyl)	H	H	2，4-Cl ₂	527
40	CH ₂	H	H	MeO	H	H	377	39	CH ₂	H	(1, the new hexyl of 1-dimethyl)	H	H	2，4-Cl ₂	527
40	CH ₂	H	H	MeO	H	H	377	41	CH ₂	H	H	MeO	H	4-Me	391
42	CH ₂	H	H	PrO	H	H	405	41	CH ₂	H	H	MeO	H	4-Me	391
42	CH ₂	H	H	PrO	H	H	405	43	CH ₂	H	H	Me	H	H	361
44	CH ₂	H	H	Cl	H	H	381	43	CH ₂	H	H	Me	H	H	361
44	CH ₂	H	H	Cl	H	H	381	45	CH ₂	H	H	H	Cl	H	381
46	CH ₂	H	H	H	Me	4-MeS	407	45	CH ₂	H	H	H	Cl	H	381
46	CH ₂	H	H	H	Me	4-MeS	407	47	CH ₂	H	H	H	Me	4-HO	377
48	CH ₂	H	H	H	Me	4-Me	375	47	CH ₂	H	H	H	Me	4-HO	377
48	CH ₂	H	H	H	Me	4-Me	375	49	CH ₂	H	H	H	Me	4-MeSO ₂	439
50	Key	H	H	H	H	H	333	49	CH ₂	H	H	H	Me	4-MeSO ₂	439
50	Key	H	H	H	H	H	333	51	(CH ₂) ₂	H	H	H	H	H	361
52	(CH ₂) ₃	H	H	H	H	H	375	51	(CH ₂) ₂	H	H	H	H	H	361
52	(CH ₂) ₃	H	H	H	H	H	375	53	OCH ₂	H	H	H	H	H	363
54	OCH ₂CH ₂	H	H	H	H	4-MeO	407	53	OCH ₂	H	H	H	H	H	363

55	NH	H	H	H	H	4-Me	361
55	NH	H	H	H	H	4-Me	361	56	NHCH ₂	H	H	H	H	H	362
57	NHCH ₂	H	H	H	H	4-Me	376	56	NHCH ₂	H	H	H	H	H	362
57	NHCH ₂	H	H	H	H	4-Me	376	58	NHCH ₂	H	H	H	H	2, the 3-benzo	412
59	NHCH ₂	H	H	H	H	4-MeO	392	58	NHCH ₂	H	H	H	H	2, the 3-benzo	412
59	NHCH ₂	H	H	H	H	4-MeO	392	60	NHCH ₂	H	H	H	H	4-CF ₃	430
61	NHCH ₂	H	H	H	H	3-Me	376	60	NHCH ₂	H	H	H	H	4-CF ₃	430
61	NHCH ₂	H	H	H	H	3-Me	376	62	NHCH ₂	H	H	H	H	4-Me ₂N	405
63	NHCH ₂	H	H	H	H	4-MeS	408	62	NHCH ₂	H	H	H	H	4-Me ₂N	405
63	NHCH ₂	H	H	H	H	4-MeS	408	64	NHCH ₂	H	H	H	H	2-Me	376
65	NHCH ₂	H	H	H	H	2，3-OCH ₂O	406	64	NHCH ₂	H	H	H	H	2-Me	376
65	NHCH ₂	H	H	H	H	2，3-OCH ₂O	406	66	NHCH ₂CH ₂	H	H	H	H	H	376

Embodiment 67 embodiment 68 embodiment 69

M+H 398 M+H 353 M+H 374

^*(R ⁶=H, unless otherwise indicated)

The embodiment numbering	A	R ¹	R ²	R ³	R ⁴	R ⁵	MS or LC/MS (M+H) ⁺
The embodiment numbering	A	R ¹	R ²	R ³	R ⁴	R ⁵	MS or LC/MS (M+H) ⁺	70	CH ₂	Me	H	H	H	4-Me	392(M+NH4)
71	CH ₂	Me	H	H	H	4-Et	387(M-H)	70	CH ₂	Me	H	H	H	4-Me	392(M+NH4)
71	CH ₂	Me	H	H	H	4-Et	387(M-H)	72	CH ₂	Me	H	H	H	4-Cl
73	CH ₂	Me	H	H	H	4-MeS		72	CH ₂	Me	H	H	H	4-Cl
73	CH ₂	Me	H	H	H	4-MeS		74	CH ₂	Me	H	H	H	4-MeO
75	CH ₂	Me	H	H	H	4-HO		74	CH ₂	Me	H	H	H	4-MeO
75	CH ₂	Me	H	H	H	4-HO		76	CH ₂	Me	H	H	H	4-MeSO ₂
77	CH ₂	Me	H	H	H	4-CF ₃O	502(M- H+MeCO2-)	76	CH ₂	Me	H	H	H	4-MeSO ₂
77	CH ₂	Me	H	H	H	4-CF ₃O	502(M- H+MeCO2-)	78	CH ₂	Me	H	H	H	4-CF ₃
79	CH ₂	Me	H	H	H	4-Ac		78	CH ₂	Me	H	H	H	4-CF ₃
79	CH ₂	Me	H	H	H	4-Ac		80	CH ₂	Me	H	H	H	4-HOCH ₂
81	CH ₂	Me	H	H	H	4-CHF ₂O		80	CH ₂	Me	H	H	H	4-HOCH ₂
81	CH ₂	Me	H	H	H	4-CHF ₂O		82	CH ₂	H	H	H	Me	4-Et
83	CH ₂	H	H	H	Me	4-CHF ₂O		82	CH ₂	H	H	H	Me	4-Et
83	CH ₂	H	H	H	Me	4-CHF ₂O		84	CH ₂	H	H	H	Me	H	378(M+NH4)
85	CH ₂	H	H	H	Me	4-Cl		84	CH ₂	H	H	H	Me	H	378(M+NH4)
85	CH ₂	H	H	H	Me	4-Cl		86	CH ₂	H	H	H	Me	4-AC
87	CH ₂	H	H	H	Me	4-HOCH ₂		86	CH ₂	H	H	H	Me	4-AC
87	CH ₂	H	H	H	Me	4-HOCH ₂		88	CH ₂	H	H	H	Me	4-CF ₃O
89	CH ₂	H	H	H	Me	4-CH ₃O	408(M+NH4)	88	CH ₂	H	H	H	Me	4-CF ₃O
89	CH ₂	H	H	H	Me	4-CH ₃O	408(M+NH4)	90	CH ₂	H	H	H	H	4-Ac
91	CH ₂	H	H	H	H	4-HOCH ₂		90	CH ₂	H	H	H	H	4-Ac
91	CH ₂	H	H	H	H	4-HOCH ₂		92	CH ₂	H	H	H	H	4-CHF ₂O

The embodiment numbering	A	R ¹	R ²	R ³	R ⁴	Heteroaryl
The embodiment numbering	A	R ¹	R ²	R ³	R ⁴	Heteroaryl	93	CH ₂	H	H	H	H	The 2-pyridine
94	CH ₂	H	H	H	H	The 3-pyridine	93	CH ₂	H	H	H	H	The 2-pyridine
94	CH ₂	H	H	H	H	The 3-pyridine	95	CH ₂	H	H	H	H	The 2-oxazole
96	CH ₂	H	H	H	H	The 2-thiazole	95	CH ₂	H	H	H	H	The 2-oxazole
96	CH ₂	H	H	H	H	The 2-thiazole	97	CH ₂	H	H	H	H	2-[4-morpholinodithio
98	CH ₂	H	H	H	H	The 3-quinoline	97	CH ₂	H	H	H	H	2-[4-morpholinodithio
98	CH ₂	H	H	H	H	The 3-quinoline	99	CH ₂	Me	H	H	H	The 2-oxazole
100	CH ₂	H	H	H	Me	The 2-thiazole	99	CH ₂	Me	H	H	H	The 2-oxazole
100	CH ₂	H	H	H	Me	The 2-thiazole	101	CH ₂	H	H	H	Me	The 2-oxazole

Claims

1. the compound with following formula structure or its pharmacy acceptable salt, its all steric isomer:

Wherein,

When Y is

Perhaps when thienyl, benzoxazolyl;

R ¹, R ², R ³And R ⁴Identical or different, independently be selected from low alkyl group, the OR of hydrogen, halogen, a 1-8 carbon atom ⁷, to methyl-benzyl, perhaps R ³, R ⁴Coupled carbon atom forms the condensed pyridyl together;

R ⁵And R ⁶Identical or different, independently be selected from low alkyl group, hydroxyl, the OR of hydrogen, halogen, a 1-8 carbon atom ⁷,-SR ⁷,-SO ₂R ⁷, CF ₃,-OCF ₃, phenyl, benzyloxy ,-OCH ₂CO ₂H ,-OCH ₂CO ₂R ⁷,-OCH ₂CONR ⁸R ⁸,-OCH ₂CH ₂NR ⁸R ⁸, perhaps R ⁵And R ⁶Coupled carbon atom forms the condensed phenyl together;

R ⁷And R ⁸It independently is the low alkyl group of 1-8 carbon atom;

A is O (CH ₂) _m, S, NH (CH ₂) _mPerhaps (CH ₂) _n, wherein n is 0-3, m is 0-2,

Have following precondition,

I) wherein A is CH ₂And Y is

And

1) works as R ²Be methyl, R ⁵Be OH, R ⁶When being the low alkyl group of 1-8 carbon atom, R ¹, R ³And R ⁴At least one of them is not a hydrogen; And

2) work as R ²When being chlorine, R ¹, R ³, R ⁴, R ⁵And R ⁶At least one of them is not a hydrogen;

Ii) wherein A is (CH ₂) _nAnd n=0, and as Y be

The time, R ¹, R ², R ³, R ⁴, R ⁵And R ⁶At least one of them is not a hydrogen;

Iii) wherein A is O (CH ₂) _mAnd m=0, Y is

And work as R ¹, R ², R ³And R ⁴In one or two be when being selected from F, Cl or Br and all the other and being hydrogen, R ⁵And R ⁶Middle none is to be selected from F, Cl or Br.

2. the compound of claim 1, wherein Y is

3. the compound of claim 1, wherein Y is thienyl or benzoxazolyl.

4. the compound of claim 1, wherein A is O (CH ₂) _m

5. the compound of claim 1, wherein A is S.

6. the compound of claim 1, wherein A is NH (CH ₂) _m

7. the compound of claim 1, wherein A is (CH ₂) _n

8. the compound that has the claim 1 of following structure:

Wherein A is CH ₂Or O or S.

9. the compound of claim 8, wherein A is CH ₂R ¹Be the low alkyl group of H, a halogen or 1-8 carbon atom, R ², R ³And R ⁵Each is hydrogen naturally.

10. the compound that has the claim 1 of following structure:

R wherein ¹Be the low alkyl group of H, a halogen or 1-8 carbon atom, perhaps R ¹And R ⁴It independently is the low alkyl group of a hydrogen or 1-8 carbon atom;

R ⁶Be 1-8 carbon atom low alkyl group or-OCF ₃

11. have the compound of the claim 1 of following structure:

Or

^*R ⁶=H, unless otherwise indicated A R ¹ R ² R ³ R ⁴ R ⁵ CH ₂ H H H H H CH ₂ H H H H 2-HO CH ₂ H H H H 4-MeO CH ₂ H H H H 4-tBu CH ₂ H H H H 4-MeS CH ₂ H H H H 4-Ph CH ₂ H H H H 4-BnO CH ₂ H H H H 4-iPr CH ₂ H H H H 4-Cl CH ₂ H H H H 4-MeSO ₂ CH ₂ H H H H 4-CF ₃ CH ₂ H H H H 4-CF ₃O CH ₂ H H H H 4-OCH ₂CO ₂H CH ₂ H H H H 4-OCH ₂CO ₂Me CH ₂ H H H H 4-OCH ₂CONEt ₂ CH ₂ H H H H 4-OCH ₂CH ₂NMe ₂ CH ₂ H H H H The 4-styryl CH ₂ H H H H 3-Me CH ₂ H H H H 3-MeO CH ₂ H H H H 2-MeO CH ₂ H H H H 2-Et CH ₂ H H H H 2，4-Me ₂ CH ₂ H H H H 3-Cl，4-Me CH ₂ Cl H H H H CH ₂ Me H H H H CH ₂ H Me H H H CH ₂ H F H H H CH ₂ H Cl H H H CH ₂ H (p-MeBn) H H H CH ₂ H Cl H H 2-HO，5-Cl CH ₂ H Cl H Br H

CH ₂ H Br H Br H CH ₂ H (1, the new hexyl of 1-dimethyl) H H 2，4-Cl ₂ CH ₂ H H MeO H H CH ₂ H H MeO H 4-Me CH ₂ H H PrO H H CH ₂ H H Me H H CH ₂ H H Cl H H CH ₂ H H H Cl H CH ₂ H H H Me 4-MeS CH ₂ H H H Me 4-HO CH ₂ H H H Me 4-Me CH ₂ H H H Me 4-MeSO ₂ Key H H H H H (CH ₂) ₂ H H H H H (CH ₂) ₃ H H H H H OCH ₂ H H H H H OCH ₂CH ₂ H H H H 4-MeO NH H H H H 4-Me NHCH ₂ H H H H H NHCH ₂ H H H H 4-Me NHCH ₂ H H H H 2, the 3-benzo NHCH ₂ H H H H 4-MeO NHCH ₂ H H H H 4-CF ₃ NHCH ₂ H H H H 3-Me NHCH ₂ H H H H 4-MeS NHCH ₂ H H H H 2-Me NHCH ₂CH ₂ H H H H H

^*R ⁶=H, unless otherwise indicated A R ¹ R ² R ³ R ⁴ R ⁵ CH ₂ Me H H H 4-Me CH ₂ Me H H H 4-Et CH ₂ Me H H H 4-CF ₃O CH ₂ H H H Me H

。

12. have the compound of the claim 1 of following structure:

^*R ⁶=H, unless otherwise indicated A R ¹ R ² R ³ R ⁴ R ⁵ CH ₂ H H H H 4-MeO CH ₂ H H H H 4-tBu CH ₂ H H H H 4-MeS

CH ₂ H H H H 4-iPr CH ₂ H H H H 4-Cl CH ₂ H H H H 4-CF ₃ CH ₂ H H H H 4-CF ₃O CH ₂ Me H H H H CH ₂ H H H Me 4-MeS CH ₂ H H H Me 4-Me CH ₂ Cl H H H H

。

13. have the compound of following structure:

^*R ⁶=H, unless otherwise indicated, wherein,

A is NHCH ₂, R ¹, R ², R ³, R ⁴In each is H, and R ⁵Be 4-Me ₂N; Or

A is NHCH ₂, R ¹, R ², R ³, R ⁴In each is H, and R ⁵Be 2,3-OCH ₂O; Or

A is CH ₂, R ¹, R ², R ³, R ⁴In each is H, and R ⁵Be 3,4-OCH ₂O.

14. a medicinal compositions, it comprises the compound and the pharmaceutically acceptable carrier of claim 1.

15. a medicinal combination, it comprises sodium dependent glucose transport protein 2 inhibitor compound and antidiabetic drug, antiadipositas drug and/or the hypolipidemic except that sodium dependent glucose transport protein 2 inhibitor of claim 1.

16. the combination of claim 15, wherein this antidiabetic drug is 1,2,3 or more kinds of biguanides, sulfonylurea, alpha-glucosidase inhibitors, peroxisome proliferation albumen activation receptor gamma agonist, peroxisome proliferation albumen activation receptor α/γ dual agonists, adipocyte-specific fatty acid binding protein-2 (aP2) inhibitor, dipeptidyl peptidase 4 inhibitor, insulin sensitizer, glucagon-like-peptide-1, Regular Insulin or meglitinide.

17. the combination of claim 16, wherein this antidiabetic drug is 1,2,3 in the following medicine or more kinds of: N1,N1-Dimethylbiguanide, Glyburide, glimepiride, Glipizide, P-607, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, Regular Insulin or repaglinide.

18. the combination of claim 15, the weight ratio of wherein said sodium dependent glucose transport protein 2 inhibitor compound and described antidiabetic drug is within 0.01 to 300: 1 scope.

19. the combination of claim 15, wherein said antiadipositas drug are 'beta '3 adrenergic agonists, lipase inhibitor, serotonin and Dopamine HCL reuptake inhibithors, thryoid receptor beta compounds and/or appetite suppressant.

20. the combination of claim 19, wherein this antiadipositas drug is orlistat, sibutramine, topiramate, Dapiclermin, Dextrofenfluramine, phentermine, Phenylpropanolamine and/or Mazindol.

21. the combination of claim 15, wherein this hypolipidemic is microsomal triglyceride transfer protein inhibitor, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, inhibitor for squalene synthetic enzyme, fiber acid derivative, the active positive regulator of low density lipoprotein receptor, lipoxygenase inhibitor or acyl-coenzyme a cholesterol acyltransferase inhibitor.

22. the combination of claim 21, wherein this hypolipidemic is Pravastatin, lovastatin, Simvastatin, Zarator, Cerivastatin, fluvastatin, fenofibrate, Ji Feibeite, clofibrate and/or avasimibe.

23. wherein there is antidiabetic drug adipocyte-specific fatty acid binding protein-2 inhibitor in the combination of claim 21, the weight ratio of adipocyte-specific fatty acid binding protein-2 inhibitor and described hypolipidemic is within 0.01 to 100: 1 scope.

24. the compound of claim 1 is used for suppressing the purposes of the medicine of sodium dependent glucose transport protein 2 in preparation.

25. the purposes of claim 24, the blood plasma level that wherein said medicine is used for the treatment of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistant, hyperglycemia, hyperinsulinemia, X syndromes, diabetic complication or free fatty acids or glycerine increases, hyperlipidaemia, obesity, hypertriglyceridemia, atherosclerosis, hypertension, perhaps is used for the high density lipoprotein increasing level.

26. the purposes of claim 24, wherein said compound has following structure:

^*R ⁶=H, unless otherwise indicated A R ¹ R ² R ³ R ⁴ R ⁵ CH ₂ H H H H 4-MeO CH ₂ H H H H 4-tBu CH ₂ H H H H 4-MeS CH ₂ H H H H 4-iPr CH ₂ H H H H 4-Cl CH ₂ H H H H 4-CF ₃ CH ₂ H H H H 4-CF ₃O CH ₂ Me H H H H CH ₂ H H H Me 4-MeS CH ₂ H H H Me 4-Me

。

27. the compound of claim 1 is used for suppressing the purposes of the medicine of sodium dependent glucose transport protein 2 in preparation, wherein said compound be use separately or with 1,2 or more kinds of other antidiabetic drug and/or 1,2 or more kinds of hypolipidemic co-administered.

28. the purposes of claim 27, wherein said medicine are used to treat Il type diabetes.